Modulators of serotonin receptors

ABSTRACT

The present invention provides modulators of serotonin receptors, pharmaceutical compositions containing such modulators and methods for treating various diseases, conditions and disorders associated with modulation of serotonin receptors such as, for example: metabolic diseases, which includes but is not limited to obesity, diabetes, diabetic complications, atherosclerosis, impared glucose tolerance and dyslipidemia; central nervous system diseases which includes but is not limited to, anxiety, depression, obsessive compulsive disorder, panic disorder, psychosis, schizophrenia, sleep disorder, sexual disorder and social phobias; cephalic pain; migraine; and gastrointestinal disorders using such compounds and compositions.

RELATED APPLICATIONS

This application claims priority benefit under Title 35 § 119(e) of U.S.Provisional Application Nos. 60/509,437 and 60/541,746, filed Oct. 7,2003 and Feb. 4, 2004, respectively, the contents of which are hereinincorporated by reference.

BACKGROUND OF THE INVENTION

The neurotransmitter/hormone serotonin (5-hydroxytryptamine, 5-HT)regulates many physiological processes via a group of at least 14distinct receptors that are organized into 7 subfamilies (Hoyer, D., etal., Pharmacol. Rev., 46, 1994). The 5-HT₂ subfamily is composed of the5-HT_(2A), 5-HT_(2B), and 5-HT_(2C) receptors as determined by genehomology and pharmacological properties. There exists a substantialcorrelation for the relationship between 5-HT₂ receptor modulation and avariety of diseases and therapies. Prior to the early 1990's the5-HT_(2C) and 5-HT_(2A) receptors were referred to as 5-HT_(1C) and5-HT₂, respectively.

The direct or indirect agonism or antagonism of 5-HT₂ receptors, eitherselectively or non-selectively, has been associated with the treatmentof various central nervous system (CNS) disorders including obesity,depression, schizophrenia and bi-polar disorders. In the recent past thecontribution of serotonergic activity to the mode of action ofanti-obesity drugs has been well documented. Compounds that increase theoverall basal tone of serotonin in the CNS have been developed asanorectic drugs. The serotonin releasing agents, such as fenfluramine,function by increasing the amount of serotonin present in the nervesynapse. These breakthrough treatments, however, are not without sideeffects. Due to the mechanism of action of serotonin releasing agents,they affect the activity of a number of serotonin receptor subtypes in awide variety of organs including those not associated with the desiredmechanism of action. This non-specific modulation of the serotoninfamily of receptors most likely plays a significant role in the sideeffect profile. In addition, these compounds or their metabolites oftenhave a high affinity for a number of the serotonin receptors as well asa multitude of other monoamine neurotransmitters and nuisance receptors.Removing some of the receptor cross reactivity would allow for theexamination and possible development of potent therapeutic ligands withan improved side effect profile.

The 5-HT_(2C) receptor is a G-protein coupled receptor. It is almostexclusively expressed in the central nervous system including thehypothalamus, hippocampus, amygdala, nucleus of the solitary tract,spinal cord, cortex, olfactory bulb, ventral tegmental area (VTA),nucleus accumbens and choroid plexus (Hoffman, B. and Mezey, E., FEBSLett., 247, 1989). There is ample evidence to support the role ofselective 5-HT_(2C) receptor ligands in a number of disease therapies.5-HT_(2C) knockout mice develop a late stage obesity syndrome that isnot reversed by fenfluramine or other direct acting 5-HT_(2C) agonistssuch as mCPP (Nonogaki, K., et al., Nature Med., 4, 1998; Vickers, S.,et. al., Psychopharmacology, 143, 1999). Administration of selective5-HT_(2C) agonists to rats causes a reduction in food intake andcorresponding reduction in body weight (Vickers, S., et al., Br. J.Pharmacol., 130, 2000) and these responses can be blocked byadministration of selective 5-HT_(2C) antagonists (Vicker, S., et al.,Neuropharmacol., 41, 2001). 5-HT_(2C) receptor modulation in thehypothalamus can also influence thermoregulation (Mazzola-Pomietto, P,et al., Psychopharmacology, 123, 1996), sleep (Sharpley, A., et al.,Neuropharmacology, 33, 1994), sexual behavior and neuroendocrinefunction (Rittenhouse, P. et al., J. Pharmacol. Exp. Ther., 271, 1994).Activation of 5-HT_(2C) receptors in the VTA modulates the activity ofdopaminergic neurons that are involved in aspects of depression (DiMatteo, V. et al., Trends Pharmacol. Sci., 22, 2001) and 5-HT_(2C)receptor agonists such as WAY 161503, RO 60-0175 and RO 60-0332 areactive in rodent models of depression (Cryan, J. and Lucki, I., J.Pharmacol. Exp. Ther., 295, 2000). 5-HT_(2C) agonists have been reportedto reduce the rewarding effects of nicotine administration in rats(Grottick, A., et al., Psychopharmacology, 157, 2001) and influencesrodent responses to cocaine administration (Grottick, A., et al., J.Pharmacol. Exp. Ther., 295, 2000). Modulation of 5-HT_(2C) receptors inthe spinal cord can influence pain perception (Chojnacka-Wojcik, E., etal., Pol. J. Pharmacol., 46, 1994). There is also data indicating thatthe 5-HT_(2C) receptor agonists mCPP and RO 60-0175 mediate penileerections in rats (Millan, M., et al., Eur J. Pharmacol. 325, 1997).

DETAILED DESCRIPTION OF THE INVENTION

The present application describes compounds according to Formula Iincluding pharmaceutically acceptable salts forms thereof, wherein A, B,D, m, n, R³, R⁸, R⁹, R¹⁰, R¹¹, W and X are described herein.Additionally, pharmaceutical compositions comprising at least onecompound according to Formula I and optionally one or more additionaltherapeutic agents are described in the present application. Finally,methods of treatment using the compounds according to Formula I bothalone and in combination with one or more additional therapeutic agentsare described in the present application.

Definitions

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

Unless otherwise indicated, the term “alkyl” as employed herein alone oras part of another group includes both straight and branched chainhydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons,more preferably 1 to 6 carbons, in the normal chain, such as, forexample, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like.

The term “alkylene” as employed herein alone or as part of another grouprefers to alkyl linking groups above having single bonds for attachmentto other groups at two different carbon atoms.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons, and morepreferably 2 to 6 carbons in the normal chain, which include one or moredouble bonds in the normal chain, such as, for example, vinyl,2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl,3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl,4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and thelike.

The term “alkenylene” and as employed herein alone or as part of anothergroup refers to alkenyl linking groups, having single bonds forattachment at two different carbon atoms.

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons and morepreferably 2 to 8 carbons in the normal chain, which include one or moretriple bonds in the normal chain, such as, for example, 2-propynyl,3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionallysubstituted with one or more functional groups as defined above foralkyl.

The term “alkynylene” as employed herein alone or as part of anothergroup refers to alkynyl linking groups, having single bonds forattachment at two different carbon atoms.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine and iodine.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group refers to saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl andtricyclic alkyl, containing a total of 3 to 20 carbons forming therings, preferably 4 to 10 carbons, forming the ring such as, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

wherein the cycloalkyl may be fused to 1 aromatic ring as described foraryl.

The term “heterocyclyl”, as used herein, refers to an unsubstituted orsubstituted stable 4-, 5-, 6- or 7-membered monocyclic ring system whichmay be saturated or unsaturated, and which consists of carbon atoms andfrom one to four heteroatoms selected from N, O, S, SO and/or SO₂ group,wherein the nitrogen heteroatoms may optionally be oxidized, and thenitrogen heteroatom may optionally be quaternized. The heterocyclic ringmay be attached at any heteroatom or carbon atom which results in thecreation of a stable structure such as, for example, piperidinyl,piperazinyl, oxopiperazinyl, oxopiperidinyl and oxadiazolyl.

The term “aryl” as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion such as, for example, phenyl or naphthyl andmay optionally include one to three additional rings fused to “aryl”such as, for example, aryl, cycloalkyl, heteroaryl or cycloheteroalkylrings.

The term “heteroaryl” as used herein refers to a 5-, 6- or 7-memberedaromatic heterocyclic ring which contains one or more heteroatomsselected from nitrogen, sulfur, oxygen and/or a SO or SO₂ group. Suchrings may be fused to another ring such as, for example, cycloalkyl,cycloheteroalkyl, aryl or heteroaryl and include possible N-oxides.

The term “oxy” as used herein as part of another group refers to anoxygen atom serving as a linker between two groups such as, for example,hydroxy, oxyalkyl, oxyalkenyl, oxyalkynyl, oxyperfluoroalkyl (e.g.—OCF₃), oxyaryl, oxyheteroaryl, oxycarboalkyl, oxycarboalkenyl,oxycarboalkynyl, oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl and aminocarboxyheteroaryl, The term “carbo” asused herein as part of another group refers to a carbonyl (C═O) groupserving as a linker between two groups such as, for example, carboalkyl,carboalkenyl, carboalkynyl, carboaryl, carboheteroaryl, carbocycloalkyl,carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxyaryl,carboxyheteroaryl, carboxycycloalkyl, oxycarboalkyl, oxycarboalkenyl,oxycarboalkynyl, oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,carboaminoalkyl, carboaminoalkenyl, carboaminoakynyl, carboaminoaryl,carboaminocycloalkyl, carboheterocyclyl, carboheteroaryl,carboaminoheterocyclyl, carboaminoheteroaryl, aminocarboalkyl,aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,aminocarboaminoheterocyclyl and aminocarboaminoheteroaryl.

The term “thio” as used herein as part of another group refers to asulfur atom serving as a linker between two groups such as, for example,thioalkyl, thioalkenyl, thioalkynyl, thioaryl, thioheteroaryl,thioheterocyclyl and thiocycloalkyl.

The term “perfluoro” as used herein as part of another group refers to agroup wherein more than one hydrogen atom attached to one or more carbonatoms in the group has been replaced with a fluorine atom such as, forexample, perfluoroalkyl (e.g. —CF₃), perfluoroalkenyl, perfluoroalkynyland oxyperfluoroalkyl.

The term “amino” as used herein alone or as part of another group refersto a nitrogen atom that may be either terminal or a linker between twoother groups, wherein the group may be a primary, secondary or tertiary(two hydrogen atoms bonded to the nitrogen atom, one hydrogen atombonded to the nitrogen atom and no hydrogen atoms bonded to the nitrogenatom, respectively) amine such as, for example, amino, aminoalkyl,aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl,alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino,cycloalkylamino, carboaminoalkyl, carboaminoalkenyl, carboaminoakynyl,carboaminoaryl, carboaminocycloalkyl, carboheterocyclyl,carboheteroaryl, carboaminoheterocyclyl, carboaminoheteroaryl,aminocarboalkyl, aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,aminocarboaminoheterocyclyl, aminocarboaminoheteroaryl, sulfoalkyl,sulfoalkenyl, sulfoalkynyl, sulfoaryl, sulfocycloalkyl,sulfoheterocyclyl and sulfoheteroaryl.

The term “nitrile” as used herein refers to a cyano (a carbon atomtriple-bonded to a nitrogen atom) group.

The term “sulfo” as used herein as part of another group refers to an—SO₂— group such as, for example, sulfoalkyl, sulfoalkenyl,sulfoalkynyl, sulfoaryl, sulfocycloalkyl, sulfoheterocyclyl andsulfoheteroaryl.

An administration of a therapeutic agent of the invention includesadministration of a therapeutically effective amount of the agent of theinvention. The term “therapeutically effective amount” as used hereinrefers to an amount of a therapeutic agent to treat or prevent acondition treatable by administration of a composition of the invention.That amount is the amount sufficient to exhibit a detectable therapeuticor preventative or ameliorative effect. The effect may include, forexample, treatment or prevention of the conditions listed herein. Theprecise effective amount for a subject will depend upon the subject'ssize and health, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombination of therapeutics selected for administration. Thus, it is notuseful to specify an exact effective amount in advance.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

The term “prodrug esters” as employed herein includes esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating agentsemploying procedures known to those skilled in the art to generateacetates, pivalates, methylcarbonates, benzoates and the like.

Various forms of prodrugs are well known in the art and are describedin:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch31, (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds. Ch 5, pgs 113–191 (Harwood Academic Publishers,1991). Said references are incorporated herein by reference.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic techniques or fractional crystallization.

The pharmaceutically acceptable salts of the compounds of formula I ofthe invention include alkali metal salts such as lithium, sodium orpotassium, alkaline earth metal salts such as calcium or magnesium, aswell as zinc or aluminum and other cations such as ammonium, choline,diethanolamine, ethylenediamine, t-butylamine, t-octylamine,dehydroabietylamine, as well as pharmaceutically acceptable anions suchas chloride, bromide, iodide, tartrate, acetate, methanesulfonate,maleate, succinate, glutarate, stearate and salts of naturally occurringamino acids such as arginine, lysine, alanine and the like, and prodrugesters thereof.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety by reference.

The novel compounds of Formula I may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including solvent,reaction atmosphere, reaction temperature, duration of the experimentand workup procedures, are chosen to be the conditions standard for thatreaction, which should be readily recognized by one skilled in the art.One skilled in the art of organic synthesis understands that thefunctionality present on various portions of the edict molecule must becompatible with the reagents and reactions proposed. Not all compoundsof Formula I falling into a given class may be compatible with some ofthe reaction conditions required in some of the methods described. Suchrestrictions to the substituents, which are compatible with the reactionconditions, will be readily apparent to one skilled in the art andalternate methods must be used.

Compounds of Formula I, wherein W is defined as a bond, may be preparedby procedures depicted in Scheme 1. Benzoic acids, which arecommercially available or can be synthesized by many syntheticmethodologies readily recognizable by one skilled in the art, can beactivated with reagents such as oxalyl chloride, thionyl chloride,dicyclohexylcarbodiimide, etc. in a suitable solvent such as methylenechloride, chloroform, tetrahydrofuran, etc. at room temperature toreflux temperature of the solvent. The activated acid can then betreated with diethylamine in a suitable solvent such as methylenechloride, chloroform, tetrahydrofuran, etc. at room temperature toreflux temperature of the solvent to yield intermediate 2. Intermediate2 can be formylated employing a base such as LDA, KHMDS, s-BuLi, etc. inTHF, ether, dioxane, etc. at −78° C. to room temperature with or withouta coordinating agent such as but not limited to TEMDA followed by theaddition of DMF. The product is then treated with a strong acid such ashydrochloric, sulfuric, etc. in a suitable solvent such as water at roomtemperature to reflux temperature of the solvent to yield intermediate3. Intermediate 3 can then be treated, according to the procedures ofWelch, J. Org. Chem. 1982, 47, 886, with intermediate 4, which arecommercially available or can be synthesized by many syntheticmethodologies readily recognized by one skilled in the art, in thepresence of sodium cyanide, sodium acatate in ethanol and acetic acid toyield intermediate 5. Cyclization can be carried out under reductivecondition with agents such as palladium, platinum, etc. with hydrogen insolvents such as ethanol, methanol, acetic acid, hydrochloric acid, etc.to yield compounds of Formula I.

Alternatively, compounds of Formula I may be synthesized by theprocedures of Ferland et al., Can. J. Chem. 1985, 63, 361 and referencetherein, with minor modifications depending on R1 which should bereadily recognized by one skilled in the art. Intermediate 3 may betreated with a nitroalkane in the presence of a base such as sodiumhydroxide, potassium hydroxide, etc. in a suitable solvent such asmethanol, ethanol, water, etc. at −20° C. to room temperature to yieldcompounds of intermediate 6. The lactone can be opened with analkylating agent such as but not limited to dimethyl sulfate in thepresence of a base such as potassium carbonte, sodium carbonate, etc. ina suitable solvent such as acetone, acetonitrile, etc. to producecompounds of intermediate 7. The lactam may be formed by the addition ofamines, intermediate 8, in the presence of weak bases such as but notlimited to sodium acetate in a suitable solvent such as acetone,acetonitrile, etc. to produce compounds of intermediate 9. Finally thecompounds can be cyclized under reductive conditions with agents such aspalladium, platinum, etc. with hydrogen in solvents such as ethanol,methanol, acetic acid, hydrochloric acid, etc., to yield compounds ofFormula I.

Alternatively, compounds of Formula I can be synthesized according toprocedures outlined in Scheme 3. Intermediate 10 can be made accordingto the synthesis described in Scheme 2 substituting ammonia forintermediate 8. Reduction of the lactam can be carried out with reagentssuch as sodium borohydride, borane, etc in a suitable solvent such asmethylene chloride, tetrahydrofuran, etc. at room temperature to refluxtemperature of the solvent to yield intermediate 11. Acylation of theamine with compounds of intermediate 12 in the presence of a base suchas triethylamine, potassium carbonate, etc. in a suitable solvent suchas methylene chloride, tetrahydrofuran, etc. to yield intermediate 13.Finally, cyclization can be accomplished by reducing the nitro groupwith reagents such palladium, platinum, etc. with hydrogen in solventssuch as ethanol, methanol, acetic acid, hydrochloric acid, etc. to yieldcompounds of Formula I.

Compounds of Formula I may also be synthesized by the proceduresoutlined in Scheme 4. Compounds of intermediate 14, which can besynthesized by the procedures of Allin et al., Tetrahedron Lett. 1999,40, 141, or Royer et al., Tetrahedron 2002, 58, 5103 and referencetherein, with minor modifications depending on R1 which should bereadily recognized by one skilled in the art, can be alkylated withintermediate 15 in the presence of a base such as triethylamine,potassium carbonate, etc. in a suitable solvent such as methylenechloride, tetrahydrofuran, etc. to yield intermediate 16. Cleavage ofthe double bond under conditions readily recognizable to one skilled inthe art, such as but not limited to ozonolysis followed but cleavage ofthe amide under basic conditions such as sodium hydroxide, lithiumhydroxide, etc in a suitable solvent such as methanol, ethanol, water,etc. produces compounds of intermediate 17. Reduction of the imine canbe accomplished with reagents such as sodium borohydride, sodiumcyanoborohydride, etc. in a suitable solvent such as methanol, methylenechloride, etc. to yield Formula I.

Compounds of Formula I, wherein W is defined as a carbon and X as acarbonyl, may be prepared by procedures depicted in Scheme 5. Aminoesters, which are commercially available or can be synthesized bymultiple synthetic methodologies readily recognizable by one skilled inthe art, using the procedures of Tang et al. Chin. J. Chem. 2002, 20,1070, can be acylated with triphosgene in a suitable solvent such asmethylene chloride, chloroform, etc. The cyclization can be thenaccomplished by treating with reagents such as but not limited toaluminum trichloride. The lactam can then be alkylated with intermediate20 in the presence of a base such as sodium hydride, NaHMDS, etc. in asuitable solvent such as ether, tetrahydrofuran, etc. to yieldintermediate 21. The ester can be reduced with reagents such as lithiumborohydride, DIBAL, etc. in a suitable solvent such as methylenechloride, methanol, etc. at room temperature to reflux temperature ofthe solvent and then oxidized to the aldehyde under conditions readilyrecognizable to one skilled in the art, such as but not limited to Swemoxidation, to yield intermediate 22. The intermediate can be cyclized tocompounds of Formula Id by removing the protecting group, Pg, with theappropriate reagents well familiar to those skilled in the art (typicalexamples may be found in Greene, T and Wuts, P. G. M., Protecting Groupsin Organic Synthesis, John Wiley & Sons, Inc., New York, N.Y., 1991 andreferences therein), and then treated with a reducing agent such assodium triacetoxyborohydride, sodium cyanoborohydride, etc.Alternatively, compounds with R1 other than H, can be synthesized bytreating intermediate 22 with R1-M, where M is a metal such as lithium,magnesium, etc., in an inert solvent such as THF, ether, etc. at −78° C.to room temperature and then oxidized to the ketone under conditionsreadily recognizable to one skilled in the art, such as but not limitedto Swern oxidation, to yield intermediate 23. Intermediate 23 can becarried forward to compounds of Formula Ie according to the proceduresdescribed above for intermediate 22.

Compounds of Formula I, wherein W is defined as a carbon and X as asubstituted carbon, may be prepared by procedures depicted in Scheme 6.Intermediate 24 can be converted to intermediate 25 under conditionsdescribed by Saxena, et al. Ind. J. Chem. 1978, 231, by treatment ofintermediate 24 with a ketone or aldehyde in the presence of an acidsuch as hydrochloric, sulfuric, etc., and then esterified underconditions readily recognizable to one skilled in the art, such as butnot limited to thionyl chloride and methanol, to yield compounds ofintermediate 25. Alternatively, compounds of Formula I, wherein W isdefined as a carbon and X as a sulfonyl, may be synthesized by theprocedures of Wells et al. J. Med. Chem., 2001, 44, 3488. Treatment ofintermediate 26 with chlorosulfonic acid in the presence of a base suchas but not limited to triethylamine and dimethylaminopyridine affordsintermediate 27. These two intermediates can then be carried forward tocompounds of Formula I using the procedures described above in Scheme 5substituting intermediate 25 or 27 for intermediate 19.

Alternatively, compounds of Formula I, wherein W is defined as a carbon,may be prepared by procedures depicted in Scheme 7. Intermediate 28,which is commercially available or can be synthesized by many syntheticmethodologies readily recognizable by one skilled in the art, can bereacted with intermediate 29, which are commercially available or can besynthesized by many synthetic methodologies readily recognizable by oneskilled in the art, in the precence of a base such as triethylamine,potassium carbonate, etc. in a suitable solvent such as methylenechloride, tetrahydrofuran, etc. to afford intermediate 30. Conversion ofthe ester to the amide can be accomplished with N,O-dimethylhydroxyamine hydrochloride in the presence of trimethyl aluminum in asuitable solvent to yield intermediate 31. This product can be cyclizedwith a base such as n-butyllithium, LDA, NaHMDS, etc. in an inertsolvent such as tetrahydrofuran, ether, etc. at −78° C. to roomtemperature to afford compounds of Formula Ia. The compound can befurther elaborated to compounds of Formula I by reducing the ketone withreagents such as but not limited to sodium borohydride or treating theketone with R10M where M is a metal such as lithium, magnesium, etc. inan inert solvent such as THF, ether, etc. at −78° C. to room temperatureto yield compounds of Formula Ib. These compounds can be reduced withreagents such as but not limited to palladium in the presence ofhydrogen to yield Formula Ic.

Alternative seven member ring compounds of Formula I can be synthesizedaccording to Scheme 7. Intermediate 22 can be homologated with thecommercially available Wittig reagent and then treated with an acid suchas hydrochloric, sulfuric, etc. to yield intermediate 32. Ifsubstitution is desired for R1 and R2, then intermediate 32 can betreated with cyclohexylamine and PTSA followed by treatment with a basesuch as LDA, KHMDS, LHMDS, etc. in THF, ether, dioxane, etc., at −78° C.to room temperature and an alkylating R1X where X is a halide, mesylate,triflate, etc. This process can be repeated to incorporate R2 ifnecessary to yield intermediate 33. The intermediates can then becarried forward to compounds of Formula I using the procedures describedabove in Scheme 5 by substituting intermediate 33 for intermediate 22.

Compounds of Formula I that contain a lactam, Schemes 1, 2, 3, 4, 5, 7,and 8, can be elaborated to form other compounds of Formula I byreduction of the carbonyl. This procedure is exemplified by thechemistry described in Scheme 9. Compounds of Formula If can be treatedwith reducing agents such but not limited to borane, lithium aluminumhydride, allane, etc. in solvent such as methylene chloride,tetrahydrofuran, etc. at room temperature to reflux temperature of thesolvent to yield Formula Ig.

Compounds of Formula I in which R3 is other than H, Scheme 10, may beprepared by reductive alkylation with an aldehyde or ketone underconditions known in the art, for example, catalytic hydrogenation withhydrogen in the presence of palladium or platinum or with reducingagents such as sodium triacetoxyborohydride. Alternatively, a similartransformation can be accomplished with an alkylating agent R3X where Xis a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. inthe presence of a base such as triethylamine, pyridine, etc. inacetonitrile, DMF, DMSO, etc. at room temperature to reflux temperatureof the solvent to yield Formula Ih.

Alternatively, compounds of Formula I can be synthesized by theprocedures outlined in Scheme 11, as exemplified by the isoindolonecore. It is understood that the aromatic substitution is shown for onlyone position on the aromatic ring and that similar transformations maybe performed at R8, R9, and R11. Compounds of Formula I can bebrominated in one of two procedures, the choice of procedures will bereadily apparent to one skilled in the art, in which the nitrogen isprotected with an amine protecting group (Pg) well familiar to thoseskilled in the art, and typical examples may be found in Greene, T andWuts, P. G. M., Protecting Groups in Organic Synthesis, John Wiley &Sons, Inc., New York, N.Y., 1991 and references therein, and thentreated with N-bromosuccinimide in a suitable solvent such as but notlimited to DMF to yield intermediate 34. Alternatively, the compound canbe treated with N-bromosuccinimide in a suitable solvent such assulfuric acid, triflouroacetic acid, etc. and then the amine protectedto yield intermediate 34. Intermediate 34 can then be modified to yieldcompounds of Formula I by boronic acid couplings, which can beaccomplished under Suzuki coupling protocols. For a review and leadingreferences of palladium catalyzed cross coupling reactions, see Miyaura,N., Suzuki, A., Chem. Rev., 1995, 2457. One such procedure entailstreatment of intermediate 34 with a functionalized aryl boronic acid inthe presence of a catalytic Pd(0) species, such as Pd(PPh₃)₄,Pd(PPh₃)₂Cl₂, Pd(OAc)₂, Pd₂(dba)₃ and a suitable ligand such as PPh₃,AsPh₃, etc., or other such Pd(0) catalyst, and a base such as Na₂CO₃,Ba(OH)₂ or Et₃N in a suitable solvent such as DMF, toluene, THF, DME orthe like, to afford intermediate 35. Removal of the protecting group,Pg, with the appropriate reagents, well familiar to those skilled in theart, and typical examples may be found in Greene, T and Wuts, P. G. M.,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc., NewYork, N.Y., 1991 and references therein, yields compounds of Formula I.

Alternatively formation of the boronic ester from intermediate 34 wouldallow for greater diversity in the subsequent coupling of this boronicacid with commercially available haloaromatic derivatives in a similarSuzuki coupling strategy as described above to afford compounds ofFormula I. One such procedure is shown in Scheme 12, as exemplified bythe isoindolone core and it is understood that the aromatic substitutionis shown for only one position on the aromatic ring and that similartransformations may be performed at R8, R9, and R11. Treatment ofintermediate 34 with a palladium catalyst such as Pd(PPh₃)₄ orPd(PPh₃)₂Cl₂ and a suitable base, a preferred one being potassiumacetate, in the presence of diboron pinacol ester affords intermediate36. This boronic ester can undergo Suzuki coupling directly with a widevariety of commercially available aryl bromides under typical Suzukiconditions as described in Scheme 10 to yield intermediate 35, which canbe deprotected as described above to afford compounds of Formula I.

Compounds of Formula I with an arylamino group attached to the aromaticring can be synthesized by the procedures outlined in Scheme 13, asexemplified by the isoindolone core and it is understood that thearomatic substitution is shown for only one position on the aromaticring and that similar transformations may be performed at R8, R9, R11.Treatment of intermediate 34 with a wide variety of commerciallyavailable anilines in the presence of a palladium (0) catalyst, such asPd₂(dba)₃, Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂, and a suitable ligand such asBINAP or PPh₃, and a base such as NaOtBu in a suitable solvent such asDMF, toluene, THF, etc. to yield intermediate 37, which can bedeprotected as described above to afford compounds of Formula I.

Alternatively, compounds of Formula I with an arylamino group attachedto the aromatic ring can be synthesized by the procedures outlined inScheme 14, as exemplified by the isoindolone core. Treatment ofintermediate 34 with benzophenone imine in the presence of a palladium(0) catalyst, such as Pd₂(dba)₃, Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂, and asuitable ligand such as BINAP or PPh₃, and a base such as NaOtBu in asuitable solvent such as DMF, toluene, THF, DME, etc., affords an iminein which nitrogen is attached to the aromatic ring. Hydrolysis of thisimine, for example with hydroxylamine and sodium acetate in methanol,affords intermediate 38. This aniline can be treated with a wide varietyof commercially available aryl bromides in the presence of a palladium(0) catalyst, such as Pd₂(dba)₃, Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂, and asuitable ligand such as BINAP or PPh₃, and a base such as but notlimited to NaOtBu in a suitable solvent such as DMF, toluene, THF, DME,etc. to yield intermediate 39, which can be deprotected as describedabove to afford compounds of Formula I.

Treatment of intermediate 38 with an appropriate aldehyde in thepresence of a suitable reducing agent such as sodiumtriacetoxyborohydride or sodium cyanoborohydride and generally undermildly acidic conditions, such as in the presence of acetic acid, in asuitable solvent such as 1,2-dichloroethane, THF, methanol oracetonitrile, yields intermediate 40. An alternate method for preparingintermediate 40 is from intermediate 34. Treatment of intermediate 34with amines in the presence of a palladium (0) catalyst, such asPd₂(dba)₃, Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂, and a suitable ligand such asBINAP or PPh₃, and a base such as NaOtBu or Na₂CO₃ in a suitable solventsuch as DMF, toluene, THF, DME, etc., affords intermediate 40. The aboveintermediates can be deprotected as described above to afford compoundsof Formula I

Treatment of intermediate 34 with an appropriate benzylzinc reagent,which can be generated from the corresponding benzyl halide, in thepresence of a palladium (O) catalyst such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, orPd₂(dba)₃, and with or without a copper (I) salt, affords intermediate41 (see Knochel, et al. Chem. Rev. 1993, 93, 2117; and Weichert, et al.Syn. Lett. 1996, 473). This chemistry can also be extended to include avariety of alkylzinc and cycloalkylzinc reagents, which are availablefrom the corresponding alkyl halides and cycloalkyl halides. The aboveintermediates can be deprotected as described above to afford compoundsof Formula I.

Compounds of Formula I with an arylhydroxy group attached to thearomatic ring can be synthesized by the procedures outlined in Scheme17, as exemplified by the isoindolone core and it is understood that thearomatic substitution is shown for only one position on the aromaticring and that similar transformations may be performed at R8, R9, R11.Intermediate 34 can be treated with various phenols in the presence of abase such as Cs₂CO₃, and a copper catalyst, such as CuPF₆(CH₃CN)₄, atelevated temperature to yield intermediate 42 (see Sawyer, Tetrahedron2000, 56, 5045). The above intermediates can be deprotected as describedabove to afford compounds of Formula I.

In addition, there exists a wide range of procedures and protocols forfunctionalizing haloaromatics, aryldiazonium and aryltriflate compounds.These procedures are well known by those in the art and described, forexample, by Stanforth, Tetrahedron, 1998, 263; Buchwald et al., J. Am.Chem. Soc., 1998, 9722; Stille, et al., J. Am. Chem. Soc., 1984, 7500.Among these procedures are biaryl couplings, alkylations, acylations,aminations, and amidations. The power of palladium catalyzedfunctionalization of aromatic cores has been explored in depth in thelast decade. An excellent review of this field can be found in J. Tsuji,“Palladium Reagents and Catalysts, Innovations in Organic Synthesis”, J.Wiley and Sons, New York, 1995.

Utilities and Combinations

Utilities

The compounds of the present invention are 5HT modulators, and includecompounds which are, for example, agonists, partial agonists,antagonists or inverse agonists of the 5HT_(2C) receptor. Accordingly,the compounds of the present invention may be useful for the treatmentor prevention of diseases and disorders associated with 5HT receptoractivity. Preferably, compounds of the present invention possessactivity as agonists of the 5HT_(2C) receptor, and may be used in thetreatment of diseases or disorders associated with the activity of the5HT_(2C) receptor.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to metabolic andeating disorders as well as conditions associated with metabolicdisorders, (e.g., obesity, diabetes, arteriosclerosis, hypertension,polycystic ovary disease, cardiovascular disease, osteoarthritis,dermatological disorders, impaired glucose hemostatsis, insulinresistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasisand sleep disorders, dislipidemic conditions, bulimia nervosa andcompulsive eating disorders); pain; sleep disorders and psychiatricdisorders, such as substance abuse, depression, anxiety, psychosis,mania and schizophrenia.

These compounds could also be used for the improvement of cognitivefunction (e.g., the treatment of dementia, including Alzheimer'sdisease, short term memory loss and attention deficit disorders);neurodegenerative disorders (e.g., Parkinson's Disease, cerebralapoplexy and craniocerebral trauma) and hypotension (e.g., hemorrhagicand endotoxin-inducd hypotension). These compounds could also be usedfor treatment of cardiac dysfunction (e.g., associated with valvulardisease, myocardial infarction, cardiac hypertrophy or congestive heartfailure); and improvement of the overall pulmonary function; transplantrejection; rheumatoid arthritis; osteoarthritis; fibromyalgia; multiplesclerosis; inflammatory bowel disease; lupus; graft vs. host disease;T-cell mediated hypersensitivity disease; psoriasis; asthma; Hashimoto'sthyroiditis; Guillain-Barre syndrome; cancer; contact dermatitis;allergic rhinitis; and ischemic or reperfusion injury. These compoundscould also be used for treatment of sexual dysfunction anderectogenesis.

Compounds useful in the treatment of appetite or motivational disordersregulate desires to consume fats, sugars, carbohydrates, alcohol ordrugs and more generally to regulate the consumption of ingredients withhedonic value. In the present description and in the claims, appetitedisorders are understood as meaning: disorders associated with asubstance and especially abuse of a substance and/or dependency on asubstance, disorders of eating behaviors, especially those liable tocause excess weight, irrespective of its origin, for example: bulimianervosa, craving for sugars. The present invention therefore furtherrelates to the use of a 5HT_(2C) receptor agonist for the treatment ofbulimia and obesity, including obesity associated with type II diabetes(non-insulin-dependent diabetes), or more generally any diseaseresulting in the patient becoming overweight. It may be due to anycause, whether genetic or environmental, including overeating andbulemia, polycycstic ovary disease, craniopharyngeoma, Prader-WilliSyndrome, Frohlich's Syndrome, Type II diabetes, growth hormonedeficiency, Turner's Syndrome and other pathological statescharacterized by reduced metabolic activity or reduced energyexpenditure. As used with reference to the utilities described herein,the term “treating” or “treatment” encompasses prevention, partialalleviation, or cure of the disease or disorder. Further, treatment ofobesity is expected to prevent progression of medical covariants ofobesity, such as arteriosclerosis, TypeII diabetes, polycystic ovarydisease, cardiovascular disease, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, cholelithiasis and sleep disorders.

Compounds in the present invention may also be useful in treatingsubstance abuse disorders, including substance dependence or abusewithout physiological dependence. Substances of abuse include alcohol,amphetamines (or amphetamine-like substances), caffeine, cannabis,cocaine, hallucinogens, inhalents, nicotine, opioids, phencyclidine (orphencyclidine-like compounds), sedative-hypnotics or benzodiazepines,and other (or unknown) substances and combinations of the above. Theterms “substance abuse disorders” also includes drug, nicotine oralcohol withdrawal syndromes and substance-induced anxiety or mooddisorder with onset during withdrawal.

Compounds in the present invention may be useful in treating memoryimpairment and cognitive disorders. The condition of memory impairmentis manifested by impairment of the ability to learn new informationand/or the inability to recall previously learned information. Memoryimpairment is a primary symptom of dementia and can also be a symptomassociated with such diseases as Alzheimer's disease, schizophrenia,Parkinson's disease, Huntington's disease, Niemann-Pick's disease,Creutzfeld-Jakob disease, attention deficit-hyperactivity disorder, HIV,cardiovascular disease such as ischemia or stroke, and head trauma aswell as age-related cognitive decline. Dementias are diseases thatinclude memory loss and additional intellectual impairment separate frommemory. 5HT_(2C) modulators may also be useful in treating cognitiveimpairments related to attentional deficits, such as attentiondeficit-hyperactivity disorders.

Compounds in the present invention may also be useful in treatingdiseases associated with dysfunction of brain dopaminergic systems, suchas Parkinson's Disease and substance abuse disorders. Parkinsons'sDisease is a neurodenerative movement disorder characterized bybradykinesia and tremor.

Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other suitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-obesity agents; anti-diabeticagents, appetite suppressants; cholesterol/lipid-lowering agents,cognition enhancing agents, agents used to treat neurodegeneration,agents used to treat respiratory conditions, agents used to treat boweldisorders, anti-inflammatory agents; anti-anxiety agents;anti-depressants; anti-psychotic agents; sedatives; hypnotics;anti-hypertensive agents; anti-tumor agents and analgesics.

Such other therapeutic agent(s) may be administered prior to,simultaneously with, or following the administration of the 5HT_(2C)modulators in accordance with the invention.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include leptin and leptin-sensitizingagents, melanocortin receptor (MC4R) agonists, agouti-related peptide(AGRP) antagonists, melanin-concentrating hormone receptor (MCHR)antagonists, growth hormone secretagogue receptor (GHSR) antagonists,orexin antagonists, CCK agonists, GLP-1 agonists, NPY1 or NPY5antagonsits, NPY2 modulators, corticotropin releasing factor agonists,histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gammamodulators, PPAR delta modulators, beta 3 adrenergic agonists, such asAJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) orother known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983 and 5,488,064, a thyroid receptor betamodulator, such as a thyroid receptor ligand as disclosed in WO 97/21993(U. Cal SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a lipaseinhibitor, such as orlistat or ATL-962 (Alizyme), leptinergics,adiponectin modulating agents, cannabinoid-1 receptor antagonists, suchas rimonabant (Sanofi) or SLV-319 (Solvay), acetyl CoA carboxylase (ACC)inhibitors as disclosed in International patent application WO 03/072197and monoamine reuptake inhibitors or releasing agents, such asfenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine,sertraline, chlorphentermine, cloforex, clortermine, picilorex,sibutramine, dexamphetamine, phentermine, phenylpropanolamine ormazindol, anorectic agents such as topiramate (Johnson & Johnson),axokine (Regeneron).

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include: insulin, which mayinclude short- and long-lasting forms as well as oral and inhaled forms,insulin secretagogues or insulin sensitizers, which may includebiguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductaseinhibitors, PPAR γ agonists such as thiazolidinediones, PPAR α agonists(such as fibric acid derivatives), PPAR δ antagonists or agonists, PPARα/γ dual agonists such as muraglitizar described in Bristol-Myers SquibbU.S. Pat. No. 6,414,002, dipeptidyl peptidase IV (DP4) inhibitors suchas BMS-477118 described in Bristol-Myers Squibb U.S. Pat. Nos. 6,395,767and 6,573,287, SGLT2 inhibitors such as the compounds described inBristol-Myers Squibb U.S. Pat. Nos. 6,414,126 and 6,515,117, glycogenphosphorylase inhibitors, and/or meglitinides, as well as insulin,and/or glucagon-like peptide-1 (GLP-1), and/or a PTP-1B inhibitor(protein tyrosine phosphatase-1B inhibitor).

The antidiabetic agent may be glucokinase inhibitors, 11 β HSDinhibitors or oral antihyperglycemic agents, which is preferably abiguanide such as metformin or phenformin or salts thereof, preferablymetformin HCl. Where the antidiabetic agent is a biguanide, thecompounds of the present invention will be employed in a weight ratio tobiguanide within the range from about 0.001:1 to about 10:1, preferablyfrom about 0.01:1 to about 5:1.

The antidiabetic agent may also preferably be a sulfonyl urea such asglyburide (also known as glibenclamide), glimepiride (disclosed in U.S.Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the beta-cells, with glyburide and glipizidebeing preferred, which may be administered in the same or in separateoral dosage forms. The oral antidiabetic agent may also be a glucosidaseinhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769) ormiglitol (disclosed in U.S. Pat. No. 4,639,436), which may beadministered in the same or in a separate oral dosage forms.

The compounds of the present invention may be employed in combinationwith a PPAR γ agonist such as a thiazolidinedione oral anti-diabeticagent or other insulin sensitizers (which has an insulin sensitivityeffect in NIDDM patients) such as troglitazone (Warner-Lambert'sREZULIN, disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB),pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No.5,594,016), Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

The compounds of the present invention may be employed in combinationwith anti-hyperlipidemia agents, or agents used to treatarteriosclerosis. An example of an hypolipidemic agent would be an HMGCoA reductase inhibitor which includes, but is not limited to,mevastatin and related compounds as disclosed in U.S. Pat. No.3,983,140, lovastatin (mevinolin) and related compounds as disclosed inU.S. Pat. No. 4,231,938, pravastatin and related compounds such asdisclosed in U.S. Pat. No. 4,346,227, simvastatin and related compoundsas disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoAreductase inhibitors which may be employed herein include, but are notlimited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772,cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080,atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929and 5,686,104, pitavastatin (Nissan/Sankyo's nisvastatin (NK-104) oritavastatin), disclosed in U.S. Pat. No. 5,011,930,Shionogi-Astra/Zeneca rosuvastatin (visastatin (ZD-4522)) disclosed inU.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S.Pat. No. 5,753,675.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol.31, No. 10, pp 1869–1871, including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,140 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243–249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291–1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544, cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40–43, 48–51, Summary, pyrrolidine derivatives as disclosed bySasyou, et al, WO 02/083636 and N-aryl-substituted cyclic aminederivatives disclosed by Okada et al, WO 02/076973.

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, α PPAR agonists, such asfenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate,clinofibrate and the like, probucol, and related compounds as disclosedin U.S. Pat. No. 3,674,836, probucol, phenylfibrate and gemfibrozilbeing preferred, bile acid sequestrants such as cholestyramine,colestipol and DEAE-Sephadex (SECHOLEX, POLICEXIDE) and cholestagel(Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (anN-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58–035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid (niacin), acipimox, acifran, neomycin, p-aminosalicylic acid,aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S.Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The other hypolipidemic agent may be an ACAT inhibitor (which also hasanti-atherosclerosis activity) such as disclosed in, Drugs of the Future24, 9–15 (1999), (Avasimibe); “The ACAT inhibitor, C1011 is effective inthe prevention and regression of aortic fatty streak area in hamsters”,Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77–85;“The pharmacological profile of FCE 27677: a novel ACAT inhibitor withpotent hypolipidemic activity mediated by selective suppression of thehepatic secretion of ApoB100-containing lipoprotein”, Ghiselli,Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16–30; “RP 73163: abioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C.,et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47–50; “ACAT inhibitors:physiologic mechanisms for hypolipidemic and anti-atheroscleroticactivities in experimental animals”, Krause et al, Editor(s): Ruffolo,Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways(1995), 173–98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors:potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med.Chem. (1994), 1(3), 204–25; “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”, Stout et al, Chemtracts:Org. Chem. (1995), 8(6), 359–62, or TS-962 (Taisho Pharmaceutical Co.Ltd), as well as F-1394, CS-505, F-12511, HL-004, K-10085 andYIC-C8-434.

The hypolipidemic agent may be an upregulator of LDL receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 (ezetimibe) as well as thosedisclosed in Atherosclerosis 115, 45–63 (1995) and J. Med. Chem. 41, 973(1998).

The other lipid agent or lipid-modulating agent may be a cholesteryltransfer protein inhibitor (CETP) such as Pfizer's Torcetrapib® as wellas those disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496,and Pharmacia's SC-744 and SC-795, as well as CETi-1 and JTT-705.

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425–430 (1999).The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

The other lipid agent also includes a phytoestrogen compound such asdisclosed in WO 00/30665 including isolated soy bean protein, soyprotein concentrate or soy flour as well as an isoflavone such asgenistein, daidzein, glycitein or equol, or phytosterols, phytostanol ortocotrienol as disclosed in WO 2000/015201; a beta-lactam cholesterolabsorption inhibitor such as disclosed in EP 675714; an HDL upregulatorsuch as an LXR agonist, a PPAR α-agonist and/or an FXR agonist; an LDLcatabolism promoter such as disclosed in EP 1022272; a sodium-protonexchange inhibitor such as disclosed in DE 19622222; an LDL-receptorinducer or a steroidal glycoside such as disclosed in U.S. Pat. No.5,698,527 and GB 2304106; an anti-oxidant such as beta-carotene,ascorbic acid, α-tocopherol or retinol as disclosed in WO 94/15592 aswell as Vitamin C and an antihomocysteine agent such as folic acid, afolate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid as disclosed inWO 97/35576; a cholesterol absorption inhibitor, an HMG-CoA synthaseinhibitor, or a lanosterol demethylase inhibitor as disclosed in WO97/48701; a PPAR δ agonist for treating dyslipidemia; or a sterolregulating element binding protein-I (SREBP-1) as disclosed in WO2000/050574, for example, a sphingolipid, such as ceramide, or neutralsphingomyelenase (N-SMase) or fragment thereof, and inhibitors or lipidsynthesis enzymes such as, for example, ACC, FAS, DGAT, MGAT, GPAT, AMPkinase, CPT1 and SCD1. Preferred dislipidemic agents are pravastatin,lovastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin,rosuvastatin, fenofibrate and Pfizer's Torcetrapib® as well as niacinand/or cholestagel.

The compounds of the present invention may be employed in combinationwith anti-hypertensive agents. Examples of suitable anti-hypertensiveagents for use in combination with the compounds of the presentinvention include beta adrenergic blockers, calcium channel blockers(L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipineand mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,bumetamide, triamtrenene, amiloride, spironolactone), renin inhibitors,ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan, candasartan and talmisartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

5HT_(2C) modulators could be useful in treating other diseasesassociated with obesity, including sleep disorders. Therefore, thecompounds described in the present invention could be used incombination with therapeutics for treating sleep disorders. Examples ofsuitable therapies for treatment of sleeping disorders for use incombination with the compounds of the present invention includemelatonin analogs, melatonin receptor agonists, ML 1 B agonists. GABA Areceptor agonists such as barbiturates (e.g., amobarbital, aprobarbital,butabarbital, mephobarbital, pentobarbital, phenobarbital, secobarbitaland talbutal), benzodiazepines (e.g., diazepam, lorazepam, oxazepam,alprazolam, chlordiazepoxide, clonazepam, chlorazepate, halazepam andprazepam), also specifically including triazolam (Halcion). Other agentsfor treating sleep disorders include zolpidem (Ambien) and Neurocrine'sindiplon.

5HT_(2C) modulators may reduce or ameliorate substance abuse oraddictive disorders. Therefore, combination of 5HT_(2C) modulators withagents used to treat addictive disorders may reduce the dose requirementor improve the efficacy of current addictive disorder therapeutics.Examples of agents used to treat substance abuse or addictive disordersare: selective serotonin reuptake inhibitors (SSR1), methadone,buprenorphine, nicotine and bupropion and opiate antagonists.

5HT_(2C) modulators may reduce anxiety or depression; therefore, thecompounds described in this application may be used in combination withanti-anxiety agents or antidepressants. Examples of suitableanti-anxiety agents for use in combination with the compounds of thepresent invention include benzodiazepines (e.g., diazepam, lorazepam,oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazepate,halazepam and prazepam), 5HT_(1A) receptor agonists (e.g., buspirone,flesinoxan, gepirone, ipsapirone and serzone), corticotropin releasingfactor (CRF) antagonists and SSRI's.

Examples of suitable classes of anti-depressants for use in combinationwith the compounds of the present invention include norepinephrinereuptake inhibitors (tertiary and secondary amine tricyclics), selectiveserotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine,paroxetine, citalopram and sertraline), monoamine oxidase inhibitors(MAOIs) (isocarboxazid, phenelzine, tranylcypromine, selegiline),reversible inhibitors of monoamine oxidase (RIMAs) (moclobemide),serotonin and norepinephrine reuptake inhibitors (SNRIs) (venlafaxine),corticotropin releasing factor (CRF) receptor antagonists (Britsol-MyersSquibb U.S. Pat. Nos. 6,642,230; 6,630,476; 6,589,952; 6,579,876;6,525,056; 6,521,636; 6,518,271; 6,515,005; 6,448,261; 6,399,609;6,362,180; and 6,358,950), alpha-adrenoreceptor antagonists, andatypical antidepressants (bupropion, lithium, nefazodone, trazodone andviloxazine).

The combination of a conventional antipsychotic drug with a 5HT_(2C)modulator could also enhance symptom reduction in the treatment ofpsychosis or mania. Further, such a combination could enable rapidsymptom reduction, reducing the need for chronic treatment withantipsychotic agents. Such a combination could also reduce the effectiveantipsychotic dose requirement, resulting in reduced probability ofdeveloping the motor dysfunction typical of chronic antipsychotictreatment.

Examples of suitable antipsychotic agents for use in combination withthe compounds of the present invention include the phenothiazine(chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine and trifluoperazine), thioxanthine(chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine,olanzepine and aripiprazole), butyrophenone (haloperidol),diphenylbutylpiperidine (pimozide) and indolone (molindolone) classes ofantipsychotic agents. Other antipsychotic agents with potentialtherapeutic value in combination with the compounds in the presentinvention include loxapine, sulpiride and risperidone.

Combination of the compounds in the present invention with conventionalantipsychotic drugs could also provide an enhanced therapeutic effectfor the treatment of schizophrenic disorders, as described above formanic disorders. As used here, schizophrenic disorders include paranoid,disorganized, catatonic, undifferentiated and residual schizophrenia,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder and psychotic disorder not specified.Examples of suitable antipsychotic drugs for combination with thecompounds in the present invention include the antipsychotics mentionedabove, as well as dopamine receptor antagonists, muscarinic receptoragonists, 5HT_(2A) receptor antagonists and 5HT_(2A)/dopamine receptorantagonists or partial agonists (e.g., olanzepine, aripiprazole,risperidone, ziprasidone).

The compounds described in the present invention could be used toenhance the effects of cognition-enhancing agents, such asacetylcholinesterase inhibitors (e.g., tacrine the active agent inCognex®), ADHD agents (e.g. methyl-phenidate, atomoxetine the activeagent in Strattera® and histamine 3 antagonists), muscarinic receptor-1agonists (e.g., milameline), nicotinic agonists, glutamic acid receptor(AMPA and NMDA) modulators such as memantine, and nootropic agents(e.g., piracetam, levetiracetam). Examples of suitable therapies fortreatment of Alzheimer's disease and cognitive disorders for use incombination with the compounds of the present invention includedonepezil, tacrine, revastigraine, 5HT6 receptor antagonists, gammasecretase inhibitors, beta secretase inhibitors, SK channel blockers,Maxi-K blockers, and KCNQs blockers.

The compounds described in the present invention could be used toenhance the effects of agents used in the treatment of Parkinson'sDisease. Examples of agents used to treat Parkinson's Disease include:levadopa with or without a COMT inhibitor, antiglutamatergic drugs(amantadine, riluzole), alpha-2 adrenergic antagonists such as idazoxan,opiate antagonists, such as naltrexone, other dopamine agonists ortransportor modulators, such as ropinirole, or pramipexole orneurotrophic factors such as glial derived neurotrophic factor (GDNF).

The compounds described in the present invention could be used incombination with agents used to treat erectile dysfunction. Examples ofsuitable treatment for erectile dysfunction include sildenafil (Viagra),vardenafil (Levitra) and tadalafil (Cialis). Other compounds that couldbe used in combination for erectile dysfunction include yohimbine,phentolamine and papaverine.

The compounds described in the present invention could be used incombination with suitable anti-inflammatory agents. Examples of suitableanti-inflammatory agents for use in combination with the compounds ofthe present invention include prednisone, dexamethasone, cyclooxygenaseinhibitors (i.e., COX-1 and/or COX-2 inhibitors such as NSAIDs, aspirin,indomethacin, ibuprofen, piroxicam, Naproxen®, Celebrex®, Vioxx®,Arcoxia®, and Bextra®), CTLA4-Ig agonists/antagonists, CD40 ligandantagonists, IMPDH inhibitors, such as mycophenolate (CellCept®),integrin antagonists, alpha4 beta-7 integrin antagonists, cell adhesioninhibitors, interferon gamma antagonists, ICAM-1 inhibitor, tumornecrosis factor (TNF) antagonists (e.g., infliximab, OR1384, includingTNF-alpha inhibitors, such as tenidap, anti-TNF antibodies or solubleTNF receptor such as etanercept (Enbrel®), Remicade®, rapamycin(sirolimus or Rapamune) and leflunomide (Arava)), prostaglandinsynthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists(e.g., priliximab), p38 mitogen-activated protein kinase inhibitors,protein tyrosine kinase (PTK) inhibitors, IKK inhibitors, and therapiesfor the treatment of irritable bowel syndrome (e.g., Zelnorm® andMaxi-K® openers such as those disclosed in U.S. Pat. No. 6,184,231 B1).

Exemplary of such other therapeutic agents which may be used incombination with 5HT_(2C) modulators include the following: cyclosporins(e.g., cyclosporin A), anti-IL-2 receptor (Anti-Tac), anti-CD45RB,anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonalantibody OKT3, agents blocking the interaction between CD40 and gp39,such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusionproteins constructed from CD40 and gp39 (CD40Ig and CD8gp39),inhibitors, such as nuclear translocation inhibitors, of NF-kappa Bfunction, such as deoxyspergualin (DSG), gold compounds,antiproliferative agents such as methotrexate, FK506 (tacrolimus,Prograf), mycophenolate mofetil, cytotoxic drugs such as azathiprine andcyclophosphamide, anticytokines such as antiIL-4 or IL-4 receptor fusionproteins and PDE 4 inhibitors such as Ariflo, and the PTK inhibitorsdisclosed in the following U.S. patent applications, incorporated hereinby reference in their entirety: Ser. No. 09/097,338, filed Jun. 15,1998; Ser. No. 09/094,797, filed Jun. 15, 1998; Ser. No. 09/173,413,filed Oct. 15, 1998; and Ser. No. 09/262,525, filed Mar. 4, 1999. Seealso the following documents and references cited therein andincorporated herein by reference: Hollenbaugh, D., Et Al, “CleavableCD40Ig Fusion Proteins and the Binding to Sgp39”, J. Immunol. Methods(Netherlands), 188(1), pp. 1–7 (Dec. 15, 1995); Hollenbaugh, D., et al,“The Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Is aLigand for the CD40 Receptor: Expression of a Soluble Form of Gp39 withB Cell Co-Stimulatory Activity”, EMBO J. (England), 11(12), pp.4313–4321 (December 1992); and Moreland, L. W. et al., “Treatment ofRheumatoid Arthritis with a Recombinant Human Tumor Necrosis FactorReceptor (P75)-Fc Fusion Protein,” New England J. of Medicine, 337(3),pp. 141–147 (1997).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The compounds of formula I of the invention can be administered orallyor parenterally, such as subcutaneously or intravenously, as well as bynasal application, transdermally, rectally or sublingually to variousmammalian species known to be subject to such maladies, e.g., humans, inan effective amount within the dosage range of about 0.2 to 1000 mg,preferably from about 1 to 100 mg in a regimen of single, two or fourdivided daily doses.

The compounds of the formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intracisternal injection or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds can, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release can be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds canalso be administered liposomally.

Exemplary compositions for oral administration include suspensions whichcan contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which can contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I can also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations can also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g. Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which can contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which can contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid, or Cremaphor.

Exemplary compositions for rectal administration include suppositorieswhich can contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

It will be understood that the specific dose level and frequency ofdosage for any particular subject can be varied and will depend upon avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the species, age, body weight, general health, sex and diet of thesubject, the mode and time of administration, rate of excretion, drugcombination, and severity of the particular condition.

Pharmacological Analysis

The pharmacological analysis of each compound for either antagonism oragonism of 5-HT_(2A, 5)-HT_(2B)and 5-HT_(2C) receptors consisted of invitro and in vivo studies. In vitro analyses included K_(i)determinations at 5-HT_(2A, 5)-HT_(2B) and 5-HT_(2C) receptors and anassessment of functional (i.e., agonism or antagonism) activity at eachreceptor class by calcium fluorecence and/or IP3 hydrolysis assays.Additional receptor assays were conducted to evaluate receptorspecificity of 5-HT_(2C) receptors over monoamine and nuisance receptors(e.g. histamine, dopamine, and muscarinic). A compound is consideredactive as a 5-HT₂ agonist if it has an EC₅₀ value or a K_(i) value ofless than about 50 micromolar; preferably less than about 1.0micromolar; more preferably less than about 0.1 micromolar. Using theassays disclosed herein, compounds of the present invention have beenshown to have an EC₅₀ value of less than about 50 micromolar for 5-HT₂agonism.

In vivo assays assessed compound activity in a variety of behavioralparadigms including acute and chronic feeding models, anxiety anddepression models (learned-helplessness, elevated plus maze,Geller-Siefter, conditioned taste aversion, taste reactivity, satietysequence). In aggregate, these models reflect activity as a 5-HT_(2C)agonist (feeding models, anxiety models, depression models) and providesome indication as to bioavailability, metabolism and pharmacokinetics.

Radioligand binding experiments were conducted on recombinant human5-HT_(2A), 5-HT_(2B), and 5-HT_(2C) receptors expressed in HEK293Ecells. The affinities of compounds of the present invention to bind atthese receptors is determined by their capacity to compete for[¹²⁵I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI) or[³H]-lysergic acid diethylamide (LSD) binding at the 5-HT_(2A),5-HT_(2B), or 5-HT_(2C) receptors. General references for binding assaysinclude 1) Lucaites V L, Nelson D L, Wainscott D B, Baez M (1996)Receptor subtype and density determine the coupling repertoire of the5-HT₂ receptor subfamily. Life Sci., 59(13):1081–95. Glennon R A, SeggelM R, Soine W H, Herrick-Davis K, Lyon R A, Titeler M (1988)[125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane: an iodinatedradioligand that specifically labels the agonist high-affinity state of5-HT2 serotonin receptors. J. Med. Chem. (1988) 31(1):5–7 and 3Leonhardt S, Gorospe E, Hoffman B J, Teitler M (1992) Molecularpharmacological differences in the interaction of serotonin with5-hydroxytryptamine 1C and 5-hydroxytryptamine2 receptors. MolPharmacol., 42(2):328–35.

The functional properties of compounds (efficacy and potency) weredetermined in whole cells expressing 5-HT_(2A), 5-HT_(2B), or 5-HT_(2C)receptors by assessing their ability to stimulate or inhibitreceptor-mediated phosphoinositol hydrolysis and/or intracellularcalcium release. The procedures used are described below.

In Vitro Binding Assays

Stable Expression of 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C) Receptors inHEK293E Cells

Stable cell lines were generated by transfecting 293EBNA cells withplasmids containing human 5-HT_(2A), 5-HT_(2B), or 5-HT_(2C) receptor(INI, INV, VNV or VGV RNA-edited isoforms) cDNA using calcium phosphate.These plasmids also contained the cytomegalovirus (CMV) immediate earlypromoter to drive receptor expression and EBV oriP for their maintenanceas an extrachromosomal element, and the hph gene from E. Coli to yieldhygromycin B resistance (Horlick et al., 1997). Transfected cells weremaintained in Dulbecco's Modified Eagle medium (DMEM) containingdialyzed 10% fetal bovine serum at 37° C. in a humid environment (5%CO₂) for 10 days. The 5-HT_(2A)cells were adapted to spinner culture forbulk processing whereas it was necessary to maintain the other lines asadherent cultures. On the day of harvest, cells were washed inphosphate-buffered saline (PBS), counted, and stored at −80° C.

Membrane Preparation

On the day of assay, pellets of whole cells (containing approximately1×10⁸ cells) expressing the 5-HT_(2A, 5)-HT_(2B) or 5-HT_(2C) receptorwere thawed on ice and homogenized in 50 mM Tris HCl (pH 7.7) containing1.0 mM EDTA using a Brinkman Polytron (PT-10, setting 6 for 10 sec). Thehomogenate was centrifuged at 48,000×g for 10 min and the resultingpellet washed twice by repeated homogenization and centrifugation steps.The final pellet was resuspended in tissue buffer and proteindeterminations were made by the bichichoninic acid (BCA) assay (PierceCo., IL) using bovine serum albumin as the standard.

Radioligand Binding Assays for the 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C)Receptors

Radioligand binding studies were conducted to determine the bindingaffinities (Ki values) of compounds for the human recombinant 5-HT_(2A),5-HT_(2B), and 5-HT_(2C) receptors (Fitzgerald et al., 1999). Assayswere conducted in disposable polypropylene 96-well plates (Costar Corp.,Cambridge, Mass.) and were initiated by the addition of 5-HT_(2A),5-HT_(2B), or 5-HT_(2C) membrane homogenate in tissue buffer (10–30μg/well) to assay buffer (50 mM Tris HCl, 0.5 mM EDTA, 10 mM pargyline,10 mM MgSO₄, 0.05% ascorbic acid, pH 7.5) containing [¹²⁵I]DOI for the5-HT_(2A) and 5-HT_(2C) receptors (0.3–0.5 nM, final) or [³H]LSD (1–2.0nM, final) for the 5-HT_(2B) receptor, with or without competing drug(i.e, newly synthesized chemical entity). For a typical competitionexperiment, a fixed concentration of radioligand was competed withduplicate concentrations of ligand (12 concentrations ranging from 10picomolar to 10 micromolar). The reaction mixtures were incubated toequilibrium for 45 min at 37° C. and terminated by rapid filtration(Packard cell harvester; Perkin-Elmer) over GFB glass-fiber filters thathad been pre-soaked in 0.3% polyethyleneimine. Filters were washed inice-cold 50 mM Tris HCl buffer (pH 7.5) and then counted on a Top Count(Packard).

Phosphoinositide Hydrolysis Studies

The ability of newly synthesized compounds to stimulate phosphoinositide(PI) hydrolysis was monitored in whole cells using a variant (Egan etal., 1998) of a protocol described previously (Berridge et al., 1982).HEK293E cells expressing the human 5-HT_(2A), 5-HT_(2B), or 5-HT_(2C)receptor were lifted with 0.5 mM EDTA and plated at a density of100,000/well onto poly-D-lysine-coated 24-well plates (Biocoat; BectonDickinson, Bedford, Mass.) in Dulbecco's modified Eagle's serum (DMEM;Gibco BRL) containing high glucose, 2 mM glutamine, 10% dialyzed fetalcalf serum, 250 μg/ml hygromycin B, and 250 μg/ml G418. Following a24–48 hr period, the growth media was removed and replaced with DMEMwithout fetal calf serum and inositol (Gibco BRL). The cells were thenincubated with DMEM (without serum and inositol) containing a finalconcentration of 0.5 uCi/well myo-[³H]inositol for 16–18 hr. Followingthis incubation, the cells were washed with DMEM (without serum orinositol) containing 10 mM LiCl and 10 μM pargyline and then incubatedfor 30 min with the same media but now containing one of several testcompounds. Reactions were terminated by aspirating the media and lysingthe cells by freeze-thaw. [³H]phosphoinositides were extracted withchloroform/methanol (1:2 v/v), separated by anion exchangechromatography (Bio-Rad AGI-X8 resin), and counted by liquidscintillation spectroscopy as described previously (Egan et al., 1998).

Calcium Fluorescence Studies

The ability of newly synthesized compounds to stimulate calciumfluorescence was monitored in whole cells using a protocol describedpreviously (Fitzgerald et al., 1999). HEK293E cells expressing the human5-HT_(2C), or 5-HT_(2B) receptor were lifted with 0.5 mM EDTA and platedat a density of 50,000/well onto poly-D-lysine-coated 96-well plates(Biocoat; Becton Dickinson, Bedford, Mass.) in Dulbecco's modifiedEagle's serum (DMEM; Gibco BRL) containing high glucose, 2 mM glutamine,10% dialyzed fetal calf serum, 250 μg/ml hygromycin B, and 250 μg/mlG418. Following a 24 hr period, the cell plates are removed from theincubator and an equal volume of Loading Buffer (Hanks BSS with 200 mMHEPES, pH 5.98) containing the calcium dye reagent (Fluo-3) is added toeach well (100 μL per well for 96-well plates and then incubated for 1hour at 37C. Following the dye loading of the cells he plates aretransferred to the FLIPR. Test compounds are added to the plate as aconcentration response curve and the changes in fluorescence units dueto calcium influx are monitored for a period of three seconds.

Data Analyses

The equilibrium apparent dissociation constants (Ki's) from thecompetition experiments were calculated using an iterative nonlinearregression curve-fitting program (Excelfit and TA Activity Base). Forthe PI hydrolysis and FLIPR experiments, EC50's were calculated using aone-site ‘pseudo’ Hill model: y=((Rmax−Rmin)/(1+R/EC50)nH))+Rmax whereR=response (GraphPad Prism; San Diego, Calif.). Emax (maximal response)was derived from the fitted curve maxima (net IP stimulation) for eachcompound. Intrinsic activity (IA) was determined by expressing the Emaxof a compound as a percentage of the Emax of 5-HT (IA=1.0).

Efficacy Models to Evaluate Food Consumption and Weight Loss

Acute overnight feeding assay. Compounds are assessed to for theirability to reduce food consumption during the dark cycle, which is themost active period of feeding in the rat. Sprague-Dawley rats aretrained on a fixed ratio three (FR3) response paradigm which requiresthem to press a bar 3 consecutive times in order to obtain a foodpellet. The number of bar presses occurring throughout the dark cyclecan be monitored electronically as a measure of food intake by theanimal. Rats are dosed orally or intraperitoneally with test compound 30minutes prior to the onset of the dark cycle. The treated animals arethen placed in individual operant boxes for 20 hours (12 hrs of darkcycle and the first 8 hours of the light cycle). Food intake in compoundtreated animals is compared to that of vehicle treated animals in orderto determine percent reductions in food intake. Simultaneousmeasurements of water intake and locomotor activity are also measuredduring the period to assess for potential adverse effects.

Chronic Feeding Assay

Compounds are assessed for their long term impact on food intake andbody weight in a three to fourteen week chronic treatment paradigm inSprague-Dawley rats (starting weight ˜450 g). Male Sprague-Dawley ratsare pre-handled for one week prior to the onset of dosing during whichtime they are also assessed for food intake behavior. Rats are thenassigned to treatment groups. Rats are dosed with vehicle or compound byoral gavage. The food intake and body weights are cumulatively assessedat the end of each treatment week and compared to vehicle treatedanimals. In some studies food intake is measured daily in order toassess the impact of reduced food consumption on pair-fed animals. Atthe end of the study period the animals are assessed for changes in bodycomposition utilizing DEXA and are then sacrificed in order to examinechanges in various blood plasma parameters.

REFERENCES

Arnt, J. Acta Pharmacol. et Toxicol. 1982: 51, 321–329.

Berridge M. J., Downes P. C., Hanley M. R. (1982) Lithium amplifiesagonist-dependent phosphotidyinositol response in brain and salivaryglands. Biochem. J., 206, 587–595.

Costall, B and Naylor, RJ. Psychopharmacology. 1975: 43, 69–74.

Egan C. T., Herrick-Davis K., Miller K., Glennon R. A., and Teitler M.(1998) Agonist activity of LSD and lisuride at cloned 5-HT_(2A) and5-HT_(2C) receptors. Psychopharmacology, 136, 409–414.

Fitzgerald L W, Conklin D S, Krause C M, Marshall A P, Patterson J P,Tran D P, Iyer G, Kostich W A, Largent B L, Hartig P R (1999)High-affinity agonist binding correlates with efficacy (intrinsicactivity) at the human serotonin 5-HT_(2A) and 5-HT_(2C) receptors:evidence favoring the ternary complex and two-state models of agonistaction. J. Neurochem., 72, 2127–2134.

Horlick, R. A., Sperle, K., Breth, L. A., Reid, C. C., Shen, E. S.,Robbinds, A. K., Cooke, G. M., Largent, B. L. (1997) Rapid Generation ofstable cell lines expressing corticotrophin-releasing hormone receptorfor drug discovery. Protein Expr. Purif. 9, 301–308.

Dosage and Formulations

The serotonin agonist and serotonin antagonist compounds of thisinvention can be administered as treatment for the control or preventionof central nervous system disorders including obesity, anxiety,depression, psychosis, schizophrenia, sleep and sexual disorders,migraine and other conditions associated with cephalic pain, socialphobias, and gastrointestinal disorders such as dysfunction of thegastrointestinal tract motility by any means that produces contact ofthe active agent with the agent's site of action, i.e., 5-HT2 receptors,in the body of a mammal. It can be administered by any conventionalmeans available for use in conjunction with pharmaceuticals, either asan individual therapeutic agent or in a combination of therapeuticagents. It can be administered alone, but preferably is administeredwith a pharmaceutical carrier selected on the basis of the chosen routeof administration and standard pharmaceutical practice.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form. Further, they mayalso be administered by internasal delivery, transdermal delivery andsuppository or depot delivery all using dosage forms well known to thoseof ordinary skill in the pharmaceutical arts.

The dosage administered will, of course, vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration; the age, health andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; and the effectdesired. By way of general guidance, a daily dosage of active ingredientcan be expected to be about 0.001 to about 1000 milligrams per kilogram(mg/kg) of body weight, with the preferred dose being about 0.01 toabout 100 mg/kg; with the more preferred dose being about 0.01 to about30 mg/kg. Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Dosage forms of compositions suitable for administration contain fromabout 0.5 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions the active ingredient will ordinarily bepresent in an amount of about 0.5–95% by weight based on the totalweight of the composition. The active ingredient can be administeredorally in solid dosage forms, such as capsules, tablets and powders, orin liquid dosage forms, such as elixirs, syrups and suspensions. It canalso be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and itssalts, and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-parabenand chlorobutanol. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, supra, a standard reference text inthis field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules A large number of unit capsules can be prepared by fillingstandard two-piece hard gelatin capsules each with 100 mg of powderedactive ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mgmagnesium stearic.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil can be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 mg of the active ingredient. The capsules should then bewashed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg of starch and 98.8 mg of lactose.Appropriate coatings may be applied to increase palatability or delayabsorption.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 25 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by injection can beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is sterilized bycommonly used techniques.

EXAMPLES Example 1 Preparation of(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

Step A. Preparation of N,N-diethyl-2-trifluoromethoxybenzamide

To a stirring solution of 2-trifluoromethoxybenzoic acid (3.6 g, 17.5mmol, Avocado) in dry CH₂Cl₂ (150 mL) with DMF (0.5 mL) was added a 2Msolution of oxalyl chloride in CH₂Cl₂ (17.5 mL) dropwise over 30 nin.The reaction was stirred for 4 h and then conc. in vacuo to a whitesolid. The solid was dissolved in CH₂Cl₂ (150 mL) and reacted withdiethylamine (3.2 g, 43.8 mmol, Aldrich) the reaction was stirred for 16h and then conc. in vacuo to a yellow solid. The solid was purified byradial chromatography (SiO₂, 1:5, EtOAc:hexanes) to yield 4.3 grams(94%) of the product as a colorless oil. MS (ESI) 262 (M+H).

Step B. Preparation ofN,N-diethyl-2-carboxaldhyde-6-trifluoromethoxybenzamide

To a stirring solution of N,N-diethyl-2-trifluoromethoxybenzamide (2260mg, 8.7 mmol) and N,N,N′,N′-tetramethylethylenediamine (1410 mg,Aldrich) in dry THF (20 mL) at −78° C. under Ar was added 0.93 Ms-butyllithium in hexanes (10.2 mL) dropwise. The reaction was stirredfor 1 h and then DMF (2.0 mL) was added. The reaction was stirred for 1h and then quenched with 1 M hydrochloric acid (15 mL). The reaction wasextracted with EtOAc (3×15 mL). The organic layers were combined, driedover Na₂SO₄, and conc in vacuo to a yellow oil. The oil was purified byradial chromatography (SiO₂, 1:4, EtOAc:hexanes) to yield 2213 mg (88%)of the product as a colorless oil. MS (ESI) 290 (M+H).

Step C. Preparation of(±)-2-[2-[(benzyloxycarbonyl)amino]ethyl]-1-carbonitrile-1,3-dihydro-4-trifluoromethoxy-isoindol-3(1H)-one

A stirring solution ofN,N-diethyl-2-carboxaldhyde-6-trifluoromethoxybenzamide (2213 mg, 7.7mmol) in 6 M hydrochloric acid (70 mL) was heated to reflux for 16 h.The reaction was cooled to room temperature and extracted with EtOAc(3×70 mL). The organic layers were combined, dried over Na₂SO₄, and concin vacuo to a brown oil. The oil (1173 mg, 5.0 mmol) was added to astirring solution of 1-(Benzyloxycarbonylamino)-2-aminoethanehydrochloride (1156 mg, 5.0 mmol, Aldrich) and sodium acatate (411 mg,5.0 mmol, Aldrich) in ethanol (13.5 mL) and acetic acid (4.5 mL)followed by sodium cyanide (245 mg, 5.0 mmol, Aldrich). The reaction wasstirred overnight and then conc in vacuo to a yellow solid. The solidwas partioned between water (10 mL) and ethyl acetate (10 mL). Theorganic layer was separated and the aqueous layer was extracted withEtOAc (3×10 mL). The organic layers were combined, dried over Na₂SO₄,and conc in vacuo to a yellow oil. The oil was purified by radialchromatography (SiO₂, 1:3, EtOAc:hexanes) to yield 1331 mg (63%) of theproduct as a colorless oil. MS (ESI) 420 (M+H).

Step D. Preparation of(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution of(±)-2-[2-[(benzyloxycarbonyl)amino]ethyl]-1-carbonitrile-1,3-dihydro-4-trifluoromethoxy-isoindol-3(1H)-one(1331 mg, 3.2 mmol) and 10% palladium on carbon (440 mg, Aldrich) inEtOH (9 mL) and HCl (1 mL) was added 80 psi of hydrogen. The reactionwas stirred for 96 h. The reaction was filtered and the filtrate wasconc. in vacuo to yield a white solid. The solid was partioned between 1M aq. NaOH (10 mL) and ethyl acetate (10 mL). The organic layer wasseparated and the aqueous layer was extracted with EtOAc (3×10 mL). Theorganic layers were combined, dried over Na₂SO₄, and conc in vacuo to apale yellow oil. The oil was purified by radial chromatography (SiO2,98:2, CH₂Cl₂:MeOH with NH₄OH) to yield 432 mg (50%) of the product as acolorless oil. MS (ESI) 273 (M+H).

Example 2 Preparation of(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution of(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(432 mg, 1.6 mmol) in dry CH₂Cl₂ (10 mL) was added di-t-butyldicarbonate (383 mg, 1.8 mmol, Aldrich). The reaction was stirred for 4h and then conc. in vacuo to a white solid. The solid was purified byradial chromatography (SiO2, 1:10, EtOAc:hexanes). The compound was thenseparated by chiral HPLC using an OD column with 80% heptane with 0.1%diethylamine and 20% 1:1 MeOH:EtOH with 0.1% diethylamine to yield 181mg of the R enantiomer and 217 mg of the S enantiomer as white solids.MS (ESI) 373 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloride

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(181 mg, 0.5 mmol) in dry ether (5 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 147 mg of awhite solid. MS (ESI) 309 (M−Cl).

Example 3 Preparation of(S)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 2 withsubstitution ofN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a] isoindol-6(2H)-one forN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-oneat Step B. MS (ESI) 309 (M−Cl).

Example 4 Preparation of(±)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 1 withsubstitution of 2-methoxybenzoic acid for 2-trifluoromethoxybenzoic acidat Step A. Final purification was accomplished by preparative LC/MSchromatography (C₁₈ column; 10–90% acetonitrile in water containing0.05% trifluoroacetic acid). MS (ESI) 219.3(M−CF₃CO₂).

Example 5 Preparation of(±)-1,3,4,10b-tetrahydro-7-fluoro-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 1 withsubstitution of 2-fluorobenzoic acid for 2-trifluoromethoxybenzoic acidat Step A. Final purification was accomplished as described in Example4. MS (ESI) 207.2 (M-CF₃CO₂).

Example 6 Preparation of(±)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 1 withsubstitution of 2-trifluoromethylbenzoic acid for2-trifluoromethoxybenzoic acid at Step A. MS (ESI) 257.3 (M+H).

Example 7 Preparation of(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 2 withsubstitution of(±)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onefor(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-oneat Step A. MS (ESI) 357.2 (M−Cl).

Example 8 Preparation of(S)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloridic acid salt

Prepared according to procedures described in Example 2 withsubstitution of(±)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onefor(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-oneat Step A. MS (ESI) 357.2 (M−Cl).

Example 9 Preparation of(±)-1,3,4,10b-tetrahydro-2-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution of(±)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(60 mg, 0.23 mmol) in water (1 mL) was added formic acid (0.22 mL, 5.9mmol) and formaldehyde (190 mg, 2.3 mmol; 37% sol. in water). Thereaction flask was sealed with a rubber septum (no nitrogen inlet) andwarmed to 60° C. The reaction was maintained at this temperature for 24h and was then cooled. The reaction was then diluted with saturatedaqueous sodium bicarbonate, washed with ethyl acetate (3×50 mL), and thecombined organic layers were dried over sodium sulfate, filtered, anconcentrated. The resulting residue was purified by radialchromatography (2% ammonium hydroxide in 8% methanol in dichloromethane)to afford the desired product (33 mg, 52%) as a pale yellow residue. MS(ESI) 271.6 (M+H).

Example 10 Preparation of(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole bishydrochloric acid salt

Step A: Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole

To a stirring solution of lithium aluminum hydride (1.12 mL, 1.12 mmol;1.0 M in THF) in dry tetrahydrofuran (1.2 mL) at 0° C. was addeddropwise sulfuric acid (0.50 mL, 0.50 mmol; 1.0 M in THF). After 1 h,N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(100 mg, 0.28 mmol) was added dropwise as a solution in tetrahydrofuran(1.2 mL). The reaction was slowly allowed to warm to room temperatureover a period of 1 h and was then quenched by the addition of water (2mL) and 1N aqueous sodium hydroxide (0.30 mL). The mixture was extractedwith ethyl acetate (×3), and the combined organic layers were dried oversodium sulfate, filtered, and concentrated. The resulting pale yellowresidue was purified by radial chromatography (30–50% ethyl acetate inhexanes) to affordN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole(37 mg, 39%) as a clear residue. MS (ESI) 343.4 (M+H).

Step B: Preparation of(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole bishydrochloric acid salt

ToN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole(37 mg, 0.11 mmmol) was added concentrated aqueous hydrogen chloride (1mL). After 15 min, the solution was concentrated, diluted with water,and lyopholized to give(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole bishydrochloric acid salt (33 mg, 99%) as an off white solid. MS (ESI)243.3 (M−HCl₂).

Example 11 Preparation of(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution of(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt (688 mg, 2.4 mmol) was added concentrated aqueoussulfuric acid (2.4 mL) and N-bromosuccinimide (420 mg, 2.4 mmol). Theresulting brown solution was covered with aluminum foil and stirred inthe dark for 24 h. The reaction was then diluted with ice water andbasified with saturated aqueous sodium bicarbonate. The resultingmixture was diluted with tetrahydrofuran (30 mL) and treated withdi-tert-butyl dicarbonate (567 mg, 2.6 mmol). After 4 h, the reactionwas washed with ethyl acetate (3×50 mL), and the combined organic layerswere dried over sodium sulfate, filtered, and concentrated. Theresulting residue was purified by radial chromatography (25% ethylacetate in hexanes) to afford the desired Boc-carbamate (878 mg, 85%) asa white foamy solid. MS (ESI) 435.2, 437.2 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

ToN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onefrom Step A (105 mg, 0.24 mmol) was added diethyl ether (2 nL) andsaturated aqueous hydrochloric acid (1 mL). After 15 min of stirring,the reaction was concentrated and treated with saturated aqueousammonium hydroxide (2 nL). The solution was concentrated to dryness andthe resulting residue was purified by radial chromatography (2% ammoniumhydroxide in 4% methanol in dichloromethane) to give a clear residue.The residue was treated with 1N aqueous hydrogen chloride andlyophilized to afford the desired product (33 mg, 37%) as an off-whitesolid. MS (ESI) 335.2, 337.2 (M−Cl).

Example 12 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To an oven-dried flask was added toluene (1.4 mL) andtris(dibenzylideneacetone) dipalladium(0) (4.8 mg, 0.005 mmol). Theresulting purple-red solution was degassed by exposing the reaction tovacuum and then an argon atmosphere (×3). Triphenylphosphine (9.7 mg,0.037 mmol) was added and the reaction was again degassed. After 5 min,N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(50 mg, 0.12 mmol) was added, and the resulting solution was degassed athird time. After 5 min, 2-methyl-4-trifluoromethoxyphenyl boronic acid(30 mg, 0.14 mmol) was added followed by aqueous sodium carbonate (0.267mL; 2M). The resulting mixture was degassed a final time and warmed toreflux conditions. The reaction was maintained under reflux conditionsfor 14 h. The mixture was then cooled, diluted with ethyl acetate (10mL) and water (10 mL), and the layers were separated. The aqueous layerwas washed with ethyl acetate (10 mL), and the combined organic extractswere dried over sodium sulfate, filtered, and concentrated. Theresulting residue was purified by radial chromatography (20–30% ethylacetate in hexanes) to give the desired Boc-carbamate (40 mg, 66%) as aclear residue. MS (ESI) 531.4 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

ToN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(11 mg, 0.022 mmol) was added diethyl ether (2 mL) and saturated aqueoushydrochloric acid (1 mL). After 15 min of stirring, the reaction wasconcentrated, diluted with water and lyopholized to give(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt (9.7 mg, 97%) as a white solid. MS (ESI) 431.3(M−Cl).

Example 13 Preparation of(R)-1,3,4,10b-tetrahydro-9-(4-methoxy-2-methylphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 12 withsubstitution of 4-methoxy-2-methylphenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. MS (ESI) 377.4(M−Cl).

Example 14 Preparation of(R)-1,3,4,10b-tetrahydro-9-(4-ethoxy-2-trifluoromethylphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 12 withsubstitution of 4-ethoxy-2-trifluoromethylphenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. MS (ESI) 445.3(M−Cl).

Example 15 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2,4-dichlorophenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 12 withsubstitution of 2,4-dichlorophenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. MS (ESI)401.2, 403.2 (M−Cl).

Example 16 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-methylthiophenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 12 withsubstitution of 2-methyl-4-methylthiophenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. MS (ESI) 393.3(M−Cl).

Example 17 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2,4-ditrifluoromethylphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 12 withsubstitution of 2,4-ditrifluoromethylphenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. MS (ESI) 469.2(M−Cl).

Example 18 Preparation of(R)-1,3,4,10b-tetrahydro-9-phenyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 12 withsubstitution of phenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. Finalpurification was accomplished by preparative LC/MS chromatography (C₁₈column; 10–90% acetonitrile in water containing 0.05% trifluoroaceticacid). MS (ESI) 333.3 (M+H).

Example 19 Preparation of(R)-1,3,4,10b-tetrahydro-9-(4-chlorophenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 12 withsubstitution of 4-chlorophenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. Finalpurification was accomplished by preparative LC/MS chromatography (C₁₈column; 10–90% acetonitrile in water containing 0.05% trifluoroaceticacid). MS (ESI) 367.3, 369.4 (M−CF₃CO₂).

Example 20 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-methylsulfonylphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 12 withsubstitution of 2-methyl-4-methylsulfonylphenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. MS (ESI) 425.3(M−Cl).

Example 21 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-chlorophenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 12 withsubstitution of 2-chlorophenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. MS (ESI)367.3, 369.3 (M−Cl).

Example 22 Preparation of(R)-1,3,4,10b-tetrahydro-9-(3-chlorophenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 12 withsubstitution of 3-chlorophenyl boronic acid for2-methyl-4-trifluoromethoxyphenyl boronic acid at Step A. MS (ESI)367.2, 369.2 (M−Cl).

Example 23 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindolebis hydrochloric acid salt

Prepared according to procedures described in Example 10 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneat Step A. MS (ESI) 417.3 (M−HCl₂).

Example 24 Preparation of(R)-1,3,4,10b-tetrahydro-9-(4-methoxy-2-methylphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindolebis trifluoroacetic acid salt

To a solution of(R)-1,3,4,10b-tetrahydro-9-(4-methoxy-2-methylphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt (38 mg, 0.09 mmol) in dry tetrahydrofuran (1 mL)was added borane in dimethylsulfide (0.087 mL, 0.92 mmol) followed bydropwise addition of lithium aluminum hydride (0.092 mL, 0.092 mmol; 1.0M in THF). After 30 min, the reaction was concentrated, quenched withaqueous hydrogen chloride (1N), and concentrated to dryness. Theresulting residue was dissolved in water and basified with solid sodiumcarbonate. The mixture was then diluted with a 1:1 solution ofacetone:methanol (10 mL) and filtered. The filtrate was concentrated andthe residue was partially purified by radial chromatography (2% ammoniumhydroxide in 4% methanol in dichloromethane).

The resulting impure free amine was dissolved in dichloromethane (10mL); excess di-tert-butyl dicarbonate (100 mg, 0.46 mmol) was thenadded. After 30 min, the reaction was concentrated and the resultingyellow residue was partially purified by radial chromatography. Theproduct was then treated with 12N aqueous hydrochloric acid (3 mL),concentrated, and finally purified by preparative LC/MS chromatography(C₁₈ column; 10–90% acetonitrile in water containing 0.05%trifluoroacetic acid) to give the desired product (8 mg, 30%) uponlyopholization. MS (ESI) 363.4 (M−CF₃CO₂—CF₃CO₂H).

Example 25 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-methylthiophenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindolebis trifluoroacetic acid salt

Prepared according to procedures described in Example 24 withsubstitution of(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-methylthiophenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt for(R)-1,3,4,10b-tetrahydro-9-(4-methoxy-2-methylphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt at Step A. MS (ESI) 379.3 (M−CF₃CO₂—CF₃CO₂H).

Example 26 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2,4-difluorophenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(50 mg, 0.12 mmol) in toluene (2 mL) was added sequentially2,4-difluoroaniline (0.035 mL, 0.35 mmol), sodium tert-butoxide (33 mg,0.35 mmol), racemic BINAP (14 mg, 0.02 mmol), andtris(dibenzylideneacetone) dipalladium(0) (7 mg, 0.007 mmol). Theresulting mixture was degassed by exposure to vacuum and then an argonatmosphere (×3) before being warmed to reflux conditions. The resultingbrown-black mixture was maintained at reflux conditions for 14 h. Thereaction was then cooled, diluted with ethyl acetate and saturatedaqueous sodium chloride. The layers were separated and the aqueous layerwas washed with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered, and concentrated. The resulting residuewas dissolved in trifluoroacetic acid (3 mL); after 20 min, the solutionwas concentrated and purified by preparative LC/MS chromatography (C₁₈column; 10–90% acetonitrile in water containing 0.05% trifluoroaceticacid) to give the desired product (4.5 mg, 6.4%) as a pale yellow solid.MS (ESI) 384.3 (M−CF₃CO₂).

Example 27 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methoxyphenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 26 withsubstitution of 2-methoxyaniline for 2,4-difluoroaniline at Step A. MS(ESI) 378.4 (M-CF₃CO₂).

Example 28 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2,4-dimethoxyphenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 26 withsubstitution of 2,4-dimethoxyaniline for 2,4-difluoroaniline at Step A.MS (ESI) 408.3 (M−CF₃CO₂).

Example 29 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-furyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindolehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-furyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a degassed solution of tetrakis(triphenylphospine)palladium(0) (3 mg,0.002 mmol) in toluene (2 mL) was addedN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(50 mg, 0.12 mmol). The resulting solution was degassed by exposure tovacuum and then an argon atmosphere (×3). To this solution was added2-(tributylstannyl)furan (0.038 mL, 0.12 mmol). The resulting solutionwas degassed a final time and was then warmed to reflux conditions. Thelight yellow solution was maintained at reflux conditions for 14 h andbecame gray in color. The reaction was cooled, diluted with ethylacetate, aqueous hydrogen chloride (1N), and saturated aqueous sodiumchloride. The layers were separated and the aqueous layer was washedwith ethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated. The resulting residue was purifiedby radial chromatography (10–30% ethyl acetate in hexanes) to give thedesired product as a clear residue (44 mg, 90%). MS (ESI) 423.3 (M+H).

Step B. Preparartion of(R)-1,3,4,10b-tetrahydro-9-(2-furyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

A stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-furyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(44 mg, 0.10 mmol) in diethyl ether (2 mL) was treated with concentratedaqueous hydrogen chloride (1 mL). The resulting mixture was stirredvigorously for 15 min and was then concentrated. Saturated aqueousammonium hydroxide (2 mL) was added, and the white mixture wasconcentrated. The resulting residue was purified by radialchromatography (2% ammonium hydroxide in 8% methanol indichloromethane); the product was then treated with aqueous hydrogenchloride (1N) and lyophilized to give the desired hydrochloric acid saltas a white solid (28 mg, 68%). MS (ESI) 323.3 (M−Cl).

Example 30 Preparation of(±)-1,3,4,10b-tetrahydro-3,3-dimethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 1 from Step C withthe substitution of 1-amino-2-(benzyloxycarbonylamino)-2-methylpropanehydrochloride for 1-(benzyloxycarbonylamino)-2-aminoethane hydrochlorideand 3-hydroxy-7-trifluoromethyl-3H-isobenzofuran-1-one for3-hydroxy-7-trifluoromethoxy-3H-isobenzofuran-1-one. MS (ESI) 285 (M+H).

Examples 31 and 32 Preparation of(3S,10bR)-1,3,4,10b-tetrahydro-3-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(3S,10bS)-1,3,4,10b-tetrahydro-3-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 1 from Step C withthe substitution of (S)-1-amino-2-(benzyloxycarbonylamino)propanehydrochloride for 1-(benzyloxycarbonylamino)-2-aminoethane hydrochlorideand 3-hydroxy-7-trifluoromethyl-3H-isobenzofuran-1-one for3-hydroxy-7-trifluoromethoxy-3H-isobenzofuran-1-one with separation ofthe diastereomers at the last step during purification. MS (ESI) 271(M−Cl).

Examples 33 and 34 Preparation of(3R,10bR)-1,3,4,10b-tetrahydro-3-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(3R,10bS)-1,3,4,10b-tetrahydro-3-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 1 from Step C withthe substitution of (R)-1-amino-2-(benzyloxycarbonylamino)propanehydrochloride for 1-(benzyloxycarbonylamino)-2-aminoethane hydrochlorideand 3-hydroxy-7-trifluoromethyl-3H-isobenzofuran-1-one for3-hydroxy-7-trifluoromethoxy-3H-isobenzofuran-1-one with separation ofthe diastereomers at the last step during purification. MS (ESI) 271(M−Cl).

Example 35 Preparation of(R)-1,3,4,10b-tetrahydro-9-phenylamino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-phenylamino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a degassed solution of tris(dibenzylideneacetone) dipalladium(0) (7mg, 0.007 mmol) and 2-(di-tert-butylphosphino)biphenyl (6 mg, 0.021mmol) in toluene (2 mL) was addedN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(50 mg, 0.115 mmol). The mixture was degassed (alternating vacuum andargon) and aniline (0.031 mL, 0.345 mmol) and sodium tert-butoxide (33mg, 0.345 mmol) were added. The mixture was degassed a final time andthen subjected to microwave conditions (150° C., 1800 sec). The mixturewas diluted with saturated aqueous sodium chloride and ethyl acetate,and the layers were separated. The aqueous layer was washed with ethylacetate (×2) and the combined organic layers were dried over sodiumsulfate, filtered, and concentrated. The resulting residue was purifiedby radial chromatography (10–20% ethyl acetate in hexanes) to give 28 mg(55%) of a pale yellow residue. MS (ESI) 448 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-phenylalino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

The product from Step A was dissolved in trifluoroacetic acid (3 mL);after 20 min, the solution was concentrated and purified by preparativeLC/MS chromatography (C₁₈ column; 10–90% acetonitrile in watercontaining 0.05% trifluoroacetic acid) to give the desired product (16mg, 50%) as a pale yellow solid upon lyopholization. MS (ESI) 348(M−CF₃CO₂).

Example 36 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-chloro-5-trifluoromethylphenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 35 from Step Awith the substitution of 2-chloro-5-trifluoromethylaniline for aniline.MS (ESI) 450.3, 452.3 (M−CF₃CO₂).

Example 37 Preparation of(R)-1,3,4,10b-tetrahydro-9-(4-trifluoromethoxyphenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 35 from Step Awith the substitution of 4-trifluoromethoxyaniline for aniline. MS (ESI)432 (M−CF₃CO₂).

Example 38 Preparation of(R)-1,3,4,10b-tetrahydro-9-(ethenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 29 from Step Awith the substitution of tributyl(vinyl)tin for2-(tributylstannyl)furan. MS (ESI) 283 (M−Cl).

Example 39 Preparation of(R)-1,3,4,10b-tetrahydro-9-acetyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 29 from Step Awith the substitution of tributyl(1-ethoxyvinyl)tin for2-(tributylstannyl)furan. MS (ESI) 299 (M−Cl).

Example 40 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt

ToN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethenyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(20 mg, 0.052) from Example 38 was added methanol (2 mL) and theresulting solution was degassed via alternating exposure to vacuum andargon. To this solution was added 10% palladium on carbon (10 mg,Aldrich) and the black suspension was subjected a hydrogen atmosphere (1atm). After 1 h, the reaction was filtered, concentrated and theresulting yellow residue was treated with concentrated aqueous hydrogenchloride (1 mL). After 15 minutes of vigorous stirring, the reactionmixture was concentrated. Saturated aqueous ammonium hydroxide (2 mL)was added, and the white mixture was concentrated. The resulting residuewas purified by radial chromatography (2% ammonium hydroxide in 8%methanol in dichloromethane) to give a clear residue. This residue wasfurther purified by preparative LC/MS chromatography (C₁₈ column; 10–90%acetonitrile in water containing 0.05% trifluoroacetic acid) to give thedesired product (9 mg, 44%) as a pale yellow solid upon lyopholization.MS (ESI) 285 (M−CF₃CO₂).

Example 41 Preparation of(R)-1,3,4,10b-tetrahydro-9-(4-isopropoxy-2-trifluoromethyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(4-isopropoxy-2-(trifluoromethy)phenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To an oven-dried flask was added toluene (2 mL) andtetrakis(triphenylphospine)palladium(0) (6 mg, 0.006 mmol). Theresulting yellow solution was degassed by exposing the reaction tovacuum and then an argon atmosphere (×3). After 5 min,N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(50 mg, 0.12 mmol) was added, and the resulting solution was degassedagain. After 5 min, 4-isopropoxy-2-(trifluoromethyl)phenyl boronic acid(31 mg, 0.13 mmol) was added followed by aqueous sodium carbonate (0.267mL; 2M). The resulting mixture was degassed a final time and warmed toreflux conditions. The reaction was maintained under reflux conditionsfor 14 h. The mixture was then cooled, diluted with ethyl acetate(10 mL)and water (10 mL), and the layers were separated. The aqueous layer waswashed with ethyl acetate (10 mL), and the combined organic extractswere dried over sodium sulfate, filtered, and concentrated. Theresulting residue was purified by radial chromatography (20–30% ethylacetate in hexanes) to give the desired Boc-carbamate (28 mg, 44%) as aclear residue. MS (ESI) 559.4 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-(4-isopropoxy-2-trifluoromethylphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

ToN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(28 mg, 0.05 mmol) was added diethyl ether (2 mL) and saturated aqueoushydrochloric acid (1 mL). After 15 minutes of vigorous stirring, thereaction mixture was concentrated. Saturated aqueous ammonium hydroxide(2 mL) was added, and the white mixture was concentrated. The resultingresidue was purified by radial chromatography (2% ammonium hydroxide in8% methanol in dichloromethane) to give a clear residue. This residuewas treated with aqueous hydrogen chloride (1 mL; 1N) and lyopholized togive(R)-1,3,4,10b-tetrahydro-9-(4-isopropoxy-2-trifluoromethylphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt (20 mg, 80%) as a white solid. MS (ESI) 459(M−Cl).

Example 42 Preparation of(S)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindole bishydrochloric acid salt

Prepared according to procedures described in Example 10 from Step Awith the substitution ofN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 243.3 (M−HCl₂).

Example 43 Preparation of(±)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation of(±)-2-(2,2-diethoxyethyl)-1-carbonitrile-1,3-dihydro-4-chloro-isoindol-3(1H)-one

Prepared according to the procedures described in Example 1, Step A–C,with the substitution of 2-chlorobenzoic acid for2-trifluoromethoxybenzoic acid in Step A and aminoacetaldehyde diethylacetal for 1-(benzyloxycarbonylamino)-2-aminoethane hydrochloride inStep C. MS (ESI) 263.3, 265.3 (M+H).

Step B. Preparation of(±)-2-(2,2-diethoxyethyl)-1-(aminomethyl)-1,3-dihydro-4-chloro-isoindol-3(1H)-one

To(±)-2-(2,2-diethoxyethyl)-1-carbonitrile-1,3-dihydro-4-chloro-isoindol-3(1H)-one(1.0 g, 3.25 mmol) in ethanol (30 mL) was added Raney 2400 Nickel (1 mL;Aldrich, slurry in water). The mixture was degassed and the reactionvessel was fitted with a hydrogen balloon. After 4 h, the mixture wasfiltered (with a water wash), concentrated, and purified by radialchromatography (2% ammonium hydroxide in 4% methanol in dichloromethane)to give the desired amino acetal as a yellow oil (640 mg, 63%). MS (ESI)267.3, 269.2 (M+H).

Step C. Preparation of(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloropyrazino[2,1-a]isoindol-6(2H)-one

To(±)-2-(2,2-diethoxyethyl)-1-(aminomethyl)-1,3-dihydro-4-chloro-isoindol-3(1H)-one(400 mg, 1.3 mmol) was added aqueous hydrogen chloride (50 mL, 1N). Theresulting mixture was stirred for 48 h. Half of this mixture (25 mL) wasbasified with sodium carbonate and then washed with 1,2-dichloroethane(×6). The combined organic layers were dried over sodium sulfate,filtered, and concentrated to a volume of approximately 50 mL. To thisyellow solution was added sodium triacetoxyborohydride (270 mg, 1.3mmol), and the resulting mixture was stirred for 24 h before beingquenched with aqueous hydrogen chloride (1N). The mixture was thenbasified with sodium carbonate, diluted with tetrahydrofuran (100 mL)and treated with excess di-tert-butyl dicarbonate (400 mg). Theresulting mixture was stirred for 1 h and was then washed withdichloromethane (×3). The combined organic layers were dried over sodiumsulfate, filtered, concentrated, and the resulting yellow residue waspurified by radial chromatography (30–50% ethyl acetate in hexanes) togive the desired(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-oneas a white solid (32 mg, 23%). MS (ESI) 323.3, 325.3 (M+H).

Step D. Preparation of(±)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloropyrazino[2,1-a]isoindol-6(2H)-one(15 mg, 0.05 mmol) was added concentrated hydrochloric acid (1 mL).After 15 min, the resulting solution was concentrated, diluted withwater, and lyopholized to give(±)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt as an off-white solid (12 mg, 100%). MS (ESI)223.2, 225.2 (M−Cl).

Example 44 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindolebis hydrochloric acid salt

Prepared according to procedures described in Example 10 from Step Awith the substitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 285.3 (M−HCl₂).

Example 45 Preparation of(±)-1,3,4,10b-tetrahydro-7-methylthio-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 43 with thesubstitution of 2-(methylthio)benzoic acid for 2-chlorobenzoic acid instep A. MS (ESI) 235.2 (M−Cl).

Examples 46 and 47 Preparation of(R)-1,3,4,9a-tetrahydro-2H-9-oxa-2,4a-diaza-anthracen-10-one and(S)-1,3,4,9a-tetrahydro-2H-9-oxa-2,4a-diaza-anthracen-10-one

Step A. Preparation of [2-(2-hydroxy-benzoylamino)-ethyl]-carbamic acidtert-butyl ester

To a stirring solution of salicylic acid (2.0 g, 14.5 mmol) and t-butylN-(2-aminoethyl)carbamate (2.32 g, 14.5 mmol) in dry THF (15 mL) wasadded a solution of 1,3-dicyclocarbodiimide (3.29 g, 16.0 mmol) inCH₂Cl₂ (5 mL) dropwise at 0° C. The reaction was stirred for 18 h andthen filtered. The filtrate was conc in vacuo. The residue was dissolvedin EtOAc (50 mL), washed with 5% NaHCO₃, dried with MgSO₄, and conc invacuo to a white solid. The solid purified by silica gel chromatography(gradient: 0–70% EtOAc in hexanes) to yield 2.88 grams (71%) of theproduct as white solid.

Step B. Preparation of N-(2-aminoethyl)-2-hydroxybenzamide

To a stirring solution of [2-(2-hydroxy-benzoylamino)-ethyl]-carbamicacid tert-butyl ester (1.0 g, 3.57 mmol) in CH₂Cl₂ (20 mL) was added 2 MHCl (10.71 mL, 21.42 mmol). The reaction was stirred for 30 min and thenconc in vacuo to yield a white solid. The solid was rinsed with Et₂O anddissolved in 20 mL of MeOH. To the solution was added DiaionWaz21 Jresin (5 g, Supelco). The solution was stirred for 30 min and thenfiltered. The filtrate was conc in vacuo to yield 629 mg (98%) of theproduct as a colorless oil. MS (ESI): 181 (M+H).

Step C. Preparation ofN-[2-(2,2-dimethoxy-ethylamino)-ethyl]-2-hydroxy-benzamide

To a solution of N-(2-aminoethyl)-2-hydroxybenzamide (332 mg, 1.85mmol), dimethoxyacetaldehyde (0.475 mL, 1.85 mmol) in CH₂Cl₂ (10 mL) wasadded sodium triacetoxyboro hydrid (588 mg, 2.80 mmol). The resultingmixture was stirred overnight, then diluted with EtOAc (50 mL), washedwith 10 mL of water and then brine, dried over MgSO₄, and conc in vacuoto yield 441 mg (97%) of the product as a colorless oil. MS (ESI) 269(M+H).

Step D. Preparation of(±)-1,3,4,9a-tetrahydro-2H-9-oxa-2,4a-diaza-anthracen-10-one

To a stirring solution ofN-[2-(2,2-dimethoxy-ethylamino)-ethyl]-2-hydroxy benzamide (300 mg, 1.11mmol) in CHCl₃ (100 mL) was added conc H₂SO₄ (2 mL). The reaction wasrefuxed overnight, then cooled to room temperature then poured into amixture of ice-saturated NaHCO₃ solution. The mixture was extracted withEtOAc (3×50 mL). The organic layers were combined, washed with brine,dried on MgSO₄, and conc in vacuo to yield a yellowish oil. The oil wasthen purified by chiral HPLC using an OD column with 10% iPrOH inheptane to yield 50 mg of the R enantiomer as white solid, MS (ESI) 205(M+H), and 56 mg of the S enantiomer as white solid, MS (ESI) 205 (M+H).

Example 59 Preparation of(±)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation of 2-chloro-4-methoxybenzoic acid

To a solution of 2-chloro-4-hydroxybenzoic acid hydrate (2.0 g, 12mmol), iodomethane (2.9 mL, 46 mmol) and N,N-dimethylformamide (50 mL)was added sodium hydride (1.9 g, 46 mmol; 60% dispersion in mineral oil)in one portion. After stirring the mixture vigorously for 16 h, thereaction was quenched with water and washed with ethyl acetate. Theaqueous layer was then acidified with aqueous hydrogen chloride (6N) togive a white precipitate. The mixture was filtered, washed with water,and the filter cake was dried in a vacuum oven to give the desired acidas an off-white solid (1.4 g, 65%). MS (ESI) 187.1, 189.1 (M+H).

Step B. Preparation of(±)-2-(2,2-diethoxyethyl)-1-carbonitrile-1,3-dihydro-4-chloro-6-methoxy-isoindol-3(1H)-one

Prepared according to the procedure described in Example 43, Step A,with the substitution of 2-chloro-4-methoxybenzoic acid for2-chlorobenzoic acid. MS (ESI) 293.2, 295.1 (M−OEt).

Step C. Preparation of(±)-N-(t-butoxycarbonyl)-2-(2,2-diethoxyethyl)-1-(aminomethyl)-1,3-dihydro-4-chloro-6-methoxy-isoindol-3(1H)-one

To(±)-2-(2,2-diethoxyethyl)-1-carbonitrile-1,3-dihydro-4-chloro-6-methoxy-isoindol-3(1H)-one(150 mg, 0.45 mmol) in ethanol (5 mL) was added Raney 2400 Nickel (0.1mL; Aldrich, slurry in water). The mixture was degassed and the reactionvessel was fitted with a hydrogen balloon. After 14 h, the mixture wasfiltered (with a water wash), concentrated, and the resulting residuewas redissolved in tetrahydrofuran (5 mL). Di-tert-butyl dicarbonate(150 mg, 0.68 mmol) was added in one portion. After 1.5 h, the reactionwas concentrated and purified by flash column chromatography (0–50%ethyl acetate in hexanes) to give the desired carbamate as a yellowresidue (193 mg, 97%). MS (ESI) 443.3, 445.3 (M+H).

Step D. Preparation of(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To(±)-2-(2,2-diethoxyethyl)-1-(aminomethyl)-1,3-dihydro-4-chloro-6-methoxy-isoindol-3(1H)-one(190 mg, 0.44 mmol) was added aqueous hydrogen chloride (5 mL, 12N).After 5 min, the solution was concentrated. The resulting residue wastreated with 1,2-dichloroethane (5 mL) and sodium triacetoxyborohydride(203 mg, 0.96 mmol). Methanol (1 mL) was added to dissolve the iminesalt. After 14 h, the reaction was concentrated, treated with aqueoushydrogen chloride (2.0 mL, 1N), and diluted with tetrahydrofuran (5 mL).Di-tert-butyl dicarbonate (190 mg, 0.87 mmol) was added in one portion,and the resulting mixture was basified with excess solid sodiumcarbonate. After stirring the resulting mixture vigorously for 1.5 h,the reaction was extracted with ethyl acetate (×3), and the combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated. The resulting residue was purified by flash columnchromatography (30% ethyl acetate in hexanes) to give the desiredproduct as a white solid (78 mg, 51%). MS (ESI) 353.2, 355.2 (M+H).

Step E. Preparation of(±)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one(20 mg, 0.06 mmol) was added concentrated hydrochloric acid (1 mL).After 15 min, the resulting solution was concentrated, diluted withwater, and lyopholized to give(±)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt as an off-white solid (15 mg, 91%). MS (ESI)253.1, 255.1 (M−Cl).

Example 60 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one

(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one(55 mg, 0.16 mmol) from Example 59, Step C, was separated by chiral HPLCusing an OD column with 80% heptane with 0.1% diethylamine and 20% 1:1MeOH:EtOH with 0.1% diethylamine to yield 16 mg (29%) of the Renantiomer and 17 mg (31%) of the S enantiomer as white solids. MS (ESI)353.3, 355.3 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloride

ToN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one(16 mg, 0.05 mmol) was added concentrated aqueous hydrochloric acid (1mL, 12N). After 1 min, the solution was concentrated, diluted withwater, and lyopholized to give a white solid (13 mg, quant). MS (ESI)253.2, 255.2 (M−Cl).

Example 61 Preparation of(S)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 60, Step B, withsubstitution ofN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 253.2, 255.2 (M−Cl).

Example 62 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 60 withsubstitution of(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-one(Example 43, Step C) for(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-oneat Step A. MS (ESI) 223.2, 225.2 (M−Cl).

Example 63 Preparation of(S)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedure described in Example 61 withsubstitution ofN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 223.2, 225.1 (M−Cl).

Example 64 Preparation of(R)-1,3,4,10b-tetrahydro-7-methylthio-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Examples 59 and 60 withsubstitution of 2-(methylthio)benzoic acid for 2-chloro-4-hydroxybenzoicacid hydrate in Example 59, Step A, and(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-methylthio-pyrazino[2,1-a]isoindol-6(2H)-one(Example 45) for(±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onein Example 60, Step A. MS (ESI) 235.2 (M−Cl).

Example 65 Preparation of(S)-1,3,4,10b-tetrahydro-7-thiomethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Examples 59 and 61 withsubstitution of 2-(methylthio)benzoic acid for 2-chloro-4-hydroxybenzoicacid hydrate in Example 59, Step A, andN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-thiomethoxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onein Example 61. MS (ESI) 235.2 (M−Cl).

Example 66 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindole bishydrochloric acid salt

Prepared according to procedures described in Example 10 from Step Awith the substitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 209.1, 211.2 (M−HCl₂).

Example 67 Preparation of(R)-1,3,4,10b-tetrahydro-9-nitrile-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-nitrile-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Zinc cyanide (8 mg, 0.07 mmol) was added to a degassed solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (Example 11, Step A),tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol), andN,N,-dimethylformamide (1 mL). The mixture was degassed again viaexposure to alternating vacuum and argon (×3) and was then subjected tomicrowave conditions (150° C., 30 min; 300W). The reaction was cooled,diluted with ethyl acetate, and the reaction was washed with 50%saturated aqueous sodium chloride. The aqueous layer was washed withethyl acetate (×2), and the combined organic layers were dried oversodium sulfate, filtered, and concentrated. The resulting residue waspurified by radial chromatography (20% ethyl acetate in hexanes) to givethe desired product as a clear residue (21 mg, 81%). MS (ESI) 382.2(M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-nitrile-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-nitrile-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onewas dissolved in diethyl ether (1 mL) and treated with concentratedaqueous hydrogen chloride (1 mL). After 1 h, the reaction wasconcentrated, diluted with water, and lyopholized to give the desriedproduct as an off-white flaky solid (14 mg, 88%). MS (ESI) 282.2 (M−Cl).

Example 68 Preparation of(±)-1,3,4,10b-tetrahydro-7-nitrile-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-nitrile-pyrazino[2,1-a]isoindol-6(2H)-one

To N-(t-butoxycarbonyl)-(O)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-one (25 mg, 0.08 mmol; Example 43, Step C) in around-bottom flask was added zinc cyanide (5 mg, 0.05 mmol),tris(dibenzylideneacetone)dipalladium(0) (1.4 mg, 0.002 mmol), and1,1′-bis(diphenylphosphino)ferrocene (1.7 mg, 0.003 mmol). To thesereagents was added N,N-dimethylacetamide (1 mL), and the resultingmixture was degassed. The reaction was then subjected to microwaveconditions (130° C., 30 min; 300W); the reaction was then cooled, andadditional zinc cyanide (0.05 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.002 mmol), and1,1′-bis(diphenylphosphino)ferrocene (0.003 mmol) were added. Thereaction was again subjected to microwave conditions (160° C., 60 min;300W). The resulting black mixture was then subjected to microwaveconditions for a final time (220° C., 60 min; 300W) before being dilutedwith tetrahydrofuran (2 mL) and treated with excess di-tert-butyldicarbonate. After 1 h, the reaction was diluted with ethyl acetate andthe mixture was washed with saturated aqueous ammonium hydroxide andsaturated aqeous sodium chloride. The organic layer was then dried oversodium sulfate, filtered, and concentrated. The resulting residue waspurified by radial chromatography (30–50% ethyl acetate in hexanes) togive the desired product as a clear residue (7 mg, 29%). MS (ESI) 314.3(M+H).

Step B. Preparation of(±)-1,3,4,10b-tetrahydro-7-nitrile-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Concentrated aqueous hydrogen chloride (1 mL) was added toN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-nitrile-pyrazino[2,1-a]isoindol-6(2H)-one(7 mg, 0.02 mmol). After 1 min, the solution was concentrated, dilutedwith water, and lyopholized to a white residue (1.0 mg, 18%). MS (ESI214.3 (M−Cl).

Example 69 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedures of Example 29, Steps A-B,substituting allyltributyltin for 2-(tributylstannyl)furan in Step A. MS(ESI) 297.3 (M−Cl).

Example 70 Preparation of(R)-1,3,4,10b-tetrahydro-9-(propyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-propyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

A mixture ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(27 mg, 0.07 mmol) and palladium on carbon (10 mg, 10 wt %; Aldrich) inmethanol (1 mL) was subjected to 1 atmosphere of hydrogen for 50 min.The reaction was then filtered, concentrated, and the resulting residuewas purified by radial chromatography (30% ethyl acetate in hexanes) togive the desired product as a clear residue (25 mg, 91%). MS (ESI) 399.4(M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-propyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

ToN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-propyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(25 mg, 0.06 mmol) was added concentrated aqueous hydrogen chloride (1mL). After 5 min, the solution was concentrated, diluted with water, andlyopholized to give the desired product as an off-white solid (19 mg,89%). %). MS (ESI) 299.3 (M−Cl).

Example 71 Preparation of(R)-1,3,4,10b-tetrahydro-9-(1-propynyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedures of Example 29, Steps A-B,substituting tributyl(1-propynyl)tin for 2-(tributylstannyl)furan inStep A. MS (ESI) 297.3 (M−Cl).

Example 72 Preparation of(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a solution of(±)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one(1.7 g, 0.008 mmol) prepared according to the procedures of Example 1,Steps A–D, substituting 2-methoxybenzoic acid for2-trifluoromethoxybenzoic acid at Step A, in tetrahydrofuran (20 mL) wasadded di-tert-butyl dicarbonate (2.5 g, 0.012 mmol). After 2 h, thesolution was concentrated and purified by flash column chromatography(50–100% ethyl acetate in hexanes) to give the desired product as awhite solid (2.4 g, quant). MS (ESI) 319.3 (M+H).

Step B. Preparation ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one(100 mg, 0.31 mmol) in dichloromethane (3 mL) at −78° C. was addeddropwise boron tribromide (0.79 mL, 0.79 mmol; 1.0M in CH₂Cl₂). After 5min, the reaction was warmed to 0° C. and an additional 0.2 mL of borontribromide (1.0 M in CH₂Cl₂) was added. After 2 h, the yellow mixturewas recooled to −78° C. and quenched with water. The reaction was warmedto room temperature and stirred for 14 h. The mixture was thenconcentrated, quenched again with aqueous hydrogen chloride (3M), andthe resulting yellow solution was concentrated to dryness. The residuewas diluted with tetrahydrofuran (10 mL) and saturated aqueous sodiumbicarbonate (1 mL). Di-tert-butyl dicarbonate (69 mg, 0.31 mmol) wasadded, and the mixture was stirred for 1 h. The reaction was thendiluted with ethyl acetate and the layers were separated. The organiclayer was then dried over sodium sulfate, fitered, and concentrated. Theresulting residue was purified by radial chromatography (20% ethylacetate in hexanes) to give the desired product as an off-white solid(86 mg, 90%). MS (ESI) 305.3 (M+H).

Step C. Preparation of(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

ToN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one(24 mg, 0.08 mmol) was added concentrated aqueous hydrogen chloride (1mL). After 5 min, the solution was concentrated, diluted with water, andlyopholized to give the desired product as an off-white solid (8 mg,42%). MS (ESI) 205.2 (M−Cl).

Example 73 Preparation of(±)-1,3,4,10b-tetrahydro-7-benzyloxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-benzyloxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one(30 mg, 0.10 mmol) from Example 72, Step B, in N,N-dimethylformamide(1.5 mL) was added benzyl bromide (0.017 L, 0.15 mmol) and potassiumcarbonate (41 mg, 0.29 mmol). The resulting mixture was warmed to 80° C.After 4 h the reaction was cooled to room temperature, diluted withethyl acetate, washed with 50% saturated aqueous sodium chloride, andthe the organic layer was dried over sodium sulfate, filtered, andconcentrated. The resulting residue was purified by radialchromatography (30% ethyl acetate in hexanes) to give the desiredproduct as a clear residue (31 mg, 80%). MS (ESI) 395.4 (M+H).

Step B. Preparation of(±)-1,3,4,10b-tetrahydro-7-benzyloxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

ToN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-benzyloxy-pyrazino[2,1-a]isoindol-6(2H)-one(31 mg, 0.08 mmol) was added concentrated aqueous hydrogen chloride (1mL). After 5 min, the solution was concentrated, treated with saturatedaqueous ammonium chloride, and reconcentrated. The resulting mixture waspurified via radial chromatography (8% methanol in dichloromethanecontaining 2% ammonium hydroxide) to give(±)-1,3,4,10b-tetrahydro-7-benzyloxy-pyrazino[2,1-a]isoindol-6(2H)-one.This material was treated with aqueous hydrogen chloride (1N),concentrated, diluted with water, and lyopholized to give the desiredproduct as an off-white solid (19 mg, 72%). MS (ESI) 295.3 (M−Cl).

Example 74 Preparation of(±)-1,3,4,10b-tetrahydro-7-isopropoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedures of Example 73, Steps A–B,substituting 2-iodopropane for benzyl bromide in Step A. MS (ESI) 247.3(M−Cl).

Example 75 Preparation of(±)-1,3,4,10b-tetrahydro-7-(2-methylpropyloxy)-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedures of Example 73, Steps A–B,substituting 1-iodo-2-methylpropane for benzyl bromide in Step A. MS(ESI) 261.3 (M−Cl).

Example 76 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-ethoxyphenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

A solution of tris(dibenzylideneacetone)dipalladium(0) (12 mg, 13 μmol)and 2-(di-tert-butylphosphino)biphenyl (12.0 mg, 40 μmol) in anhydroustoluene (5 mL) was degassed with argon for 15 min at room temperature,thenN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(93 mg, 0.21 mmol) was added. Upon further degassing, 2-ethoxyaniline(88 mg, 0.64 mmol) and sodium tert-butoxide (61 mg, 0.64 mmol) wereadded. The mixture was degassed a final time and then subjected tomicrowave conditions (150 W, 150° C.) for 1 h. Upon cooling to roomtemperature, the mixture was filtered through a bilayer pad ofdiatomaceous earth and silica gel using 1:1 hexanes/EtOAc (500 mL) towash the pad. The filtrate was concentrated in vacuo and the residue waspurified by flash column chromatography (silica gel, 5–60% Et₂O/hexanes)to provide the corresponding N-linked oxoisoindole (55 mg) in 52% yield.A solution of the Boc-protected oxoisoindole in CH₂Cl₂ (10 mL) at −10°C. was treated with TFA (3 mL) and stirred for 3 h. Upon concentrationin vacuo, the residue was partitioned between CH₂Cl₂ (50 mL) and satdNaHCO₃ (50 mL). The aqueous phase was extracted with CH₂Cl₂ (4×75 mL).The combined organic phases were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography [silica gel, 5–33% (80:18:2 CHCl₃/MeOH/concdNH₄OH)/CH₂Cl₂] and trituration with CH₂Cl₂/Et₂O/hexanes to provide thedesired product (24 mg, 63%) as a white solid. MS (APCI) 392 (M+H).

Example 77 Preparation of(R)-1,3,4,10b-tetrahydro-9-(4-fluoro-3-methylphenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 76 withsubstitution of 4-fluoro-2-methylaniline for 2-ethoxyaniline. MS (APCI)380 (M+H).

Example 78 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2,5-dichlorophenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 76 withsubstitution of 2,5-dichloroaniline for 2-ethoxyaniline. MS (APCI) 416(M+H).

Example 79 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-fluorophenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 76 withsubstitution of 2-fluoroaniline for 2-ethoxyaniline. MS (APCI) 366(M+H).

Example 80 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2,3-difluorophenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 76 withsubstitution of 2,3-difluoroaniline for 2-ethoxyaniline. MS (APCI) 384(M+H).

Example 81 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-fluoro-4-methoxyphenyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 76 withsubstitution of 2-fluoro-4-methoxyaniline for 2-ethoxyaniline. MS (APCI)396 (M+H).

Example 82 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methoxy-3-pyridinyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 76 withsubstitution of 3-amino-2-methoxypyridine for 2-ethoxyaniline. MS (APCI)379 (M+H).

Example 83 Preparation of(R)-1,3,4,10b-tetrahydro-9-(4-fluoro-5-methyl-3-pyridinyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 76 withsubstitution of 5-amino-2-fluoro-3-methylpyridine for 2-ethoxyaniline atStep A. MS (APCI) 381 (M+H).

Example 84 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-ethoxy-3-pyridinyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

A solution of tris(dibenzylideneacetone)dipalladium(0) (14 mg, 15 μmol)and 2-(di-tert-butylphosphino)biphenyl (14.0 mg, 46 μmol) in anhydroustoluene (5.5 mL) was degassed with argon for 15 min at room temperature,thenN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(110 mg, 0.25 mmol) was added. Upon further degassing, benzophenoneimine (0.14 mg, 0.75 mmol) and sodium tert-butoxide (73 mg, 0.75 mmol)were added. The mixture was degassed a final time and then subjected tomicrowave conditions (150 W, 150° C.) for 1 h. Upon cooling to roomtemperature, the mixture was filtered through a pad of diatomaceousearth and the pad was washed with EtOAc (100 mL). The filtrate wasconcentrated in vacuo and the residue was dissolved in MeOH (10 mL) andcooled to 0° C. To this solution was added sodium acetate (95 mg, 1.4mmol) and hydroxylamine hydrochloride (150 mg, 1.8 mmol). The reactionwas warmed to room temperature and stirred for 1.5 h. Additional amountsof sodium acetate (95 mg, 1.4 mmol) and hydroxylamine hydrochloride (150mg, 1.8 mmol) were added at 0° C. and the reaction was stirred at roomtemperature for an additional 2.5 h. The solution was concentrated invacuo and the residue was partitioned between CH₂Cl₂ (50 mL) and 1 NNaOH (50 mL). The aqueous phase was extracted with CH₂Cl₂ (4×75 mL). Thecombined organic phases were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 5–33% EtOAc/hexanes) to provide the product(47 mg) in 50% yield. MS (APCI) 372 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-ethoxy-3-pyridinyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

A solution of tris(dibenzylideneacetone)dipalladium(0) (12 mg, 13 μmol)and 2-(di-tert-butylphosphino)biphenyl (12.0 mg, 40 μmol) in anhydroustoluene (5 mL) was degassed with argon for 15 min at room temperature,then 3-bromo-2-ethoxypyridine (33 mg, 0.16 mmol) was added. Upon furtherdegassing,N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (66 mg, 0.18 mmol) and sodium tert-butoxide (26mg, 0.27 mmol) were added. The mixture was degassed a final time andthen subjected to microwave conditions (150 W, 150° C.) for 1 h. Uponcooling to room temperature, the mixture was filtered through a pad ofdiatomaceous earth and the pad was washed with EtOAc (100 mL). Thefiltrate was concentrated in vacuo and the residue was purified by flashcolumn chromatography (silica gel, 5–60% Et₂O/hexanes) to provide thecorresponding N-linked oxoisoindole (35 mg) in 44% yield. A solution ofthe Boc-protected oxoisoindole in CH₂Cl₂ (10 mL) at −10° C. was treatedwith TFA (3 mL) and stirred for 2.5 h. Upon concentration in vacuo, theresidue was purified by preparative HPLC (Varian Dynamax C18 column,10–100% CH₃CN/H₂O with 0.05% TFA) followed by trituration of thecombined fractions with CH₂Cl₂/Et₂O/hexanes to provide the product (9mg, 25%) as a yellow solid: MS (APC1) 393 (M+H).

Example 85 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-isopropoxy-5-methyl-3-pyridinyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 84 withsubstitution of 3-bromo-2-isopropoxy-5-methylpyridine for3-bromo-2-ethoxypyridine at Step B. MS (APCI) 421 (M+H).

Example 86 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-isopropoxy-4-methyl-3-pyridinyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 84 withsubstitution of 3-bromo-2-isopropoxy-4-methylpyridine for3-bromo-2-ethoxypyridine at Step B. MS (APCI) 421 (M+H).

Example 87 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-ethoxy-5-methyl-3-pyridinyl)amino-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 84 withsubstitution of 3-bromo-2-ethoxy-5-methylpyridine for3-bromo-2-ethoxypyridine at Step B. MS (APCI) 421 (M+H).

Example 88 Preparation of(4R,10bR)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation of2-(1-cyano-3-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid tert-butyl ester

To a stirring solution of3-hydroxy-7-trifluoromethyl-3H-isobenzofuran-1-one (436 mg, 2 mmol) andsodium acetate (164 mg, 2 mmol) in ethanol (6 mL) and acetic acid (2 mL)was added R-tert-butyl 2-aminopropanoate hydrochloride (363 mg, 2 mmol)ans sodium cyanide (98 mg, 2 mmol). The reaction was stirred overnightand then conc in vacuo to a yellow solid. The solid was partionedbetween water and ethyl acetate. The organic layer was separated and theaqueous phase was extracted with ehtyl acetate (2×10 mL). The organiclayers were combined, dried over Na₂SO₄, and conc. in vacuo to a yellowoil. The oil was purified by radial chromatography (silica gel, 3:1hexanes:EtOAc) to give 390 mg of the desired product as a pale yellowoil. MS (ESI) 355 (M+H).

Step B. Preparation of2-(1-aminomethyl-3-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid hydrochloride

A stirring degassed solution of2-(1-cyano-3-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid tert-butyl ester (390 mg, 1.1 mmol) and 10% palladium on carbon (20mg) in methanol (10 mL) and conc. hydrocloric acid (1 mL) was added 80psi of hydrogen. The reaction was stirred for 4 h and then filtered. Thefiltrated was conc. in vacuo to a white solid. The solid was dissolvedin water and lypholized to give 352 mg of the desired product as a whitesolid. MS (ESI) 303 (M−Cl).

Step C. Preparation of(4R,10bS)-1,3,4,10b-tetrahydro-4-methyl-3-oxo-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-oneand(4R,10bR)-1,3,4,10b-tetrahydro-4-methyl-3-oxo-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

A stirring solution of2-(1-aminomethyl-3-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid hydrochloride (185 mg, 0.55 mmol) and triethylamine (268 mg, 2.65mmol) in dry DMF (10 mL) was addedbenzotriazol-1-yloxy-tris(pyrrolodinyl)-phosphonium hexafluorophosphate(354 mg, 0.68 mmol). The reaction was stirred for 4 h and then conc. invacuo to a yellow oil. The oil was partioned between water and ethylacetate. The organic layer was separated, dried over Na₂SO₄, and conc.in vacuo to a yellow solid. The solid was purified by radialchromatography (silica gel, EtOAc) to give 84 mg of the desired productas a white solid. MS (ESI) 285 (M+H).

Step D. Preparation ofN-(t-butoxycarbonyl)-(4R,10bR)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

A stirring solution of(4R,10bS)-1,3,4,10b-tetrahydro-4-methyl-3-oxo-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-oneand(4R,10bR)-1,3,4,10b-tetrahydro-4-methyl-3-oxo-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(84 mg, 0.3 mmol) in dry THF (3 mL) was added 1 M borane in THF (1.5mL). The reaction was heated to reflux for 16 h and then cooled to roomtemperature. The reaction was quenched with conc. hydrochloric acid (1mL) and heated to reflux for 1 h. The reaction was conc. in vacuo to awhite solid. The solid was dissovled in THF and made basic with 1 M aqNaOH. The reaction was then treated with di-tert-butyl dicarbonate (87mg, 0.4 mmol) for 3 h. The reaction was extracted with EtOAc (3×5 mL).The organic layers were combined, dried over Na₂SO₄, and conc. in vacuoto a colorless oil. The oil was purified by radial chromatography(silica gel, 7:1 hexanes:EtOAc) to give 32 mg of the desired product asa white solid and 32 mg ofN-(t-butoxycarbonyl)-(4R,10bS)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-oneas a colorless oil. MS (ESI) 371 (M+H).

Step E. Preparation of(4R,10bR)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(4R,10bR)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(30mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL).The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 21 mg of awhite solid. MS (ESI) 271 (M−Cl).

Example 89 Preparation of(4R,10bS)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 88 withsubstitution ofN-(t-butoxycarbonyl)-(4R,10bS)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-oneat Step E. MS (ESI) 271 (M−Cl).

Example 90 Preparation of(4S,10bS)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 88 withsubstitution of S-tert-butyl 2-aminopropanoate hydrochloride forR-tert-butyl 2-aminopropanoate hydrochloride at Step A. MS (ESI) 271(M−Cl).

Example 91 Preparation of(4S,10bR)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 88 withsubstitution of S-tert-butyl 2-aminopropanoate hydrochloride forR-tert-butyl 2-aminopropanoate hydrochloride at Step A. MS (ESI) 271(M−Cl).

Example 92 Preparation of(4S,10bS)-1,3,4,10b-tetrahydro-4-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 88 withsubstitution of S-tert-butyl 2-amino-3-methylbutanoate hydrochloride forR-tert-butyl 2-aminopropanoate hydrochloride at Step A. MS (ESI) 299(M−Cl).

Example 93 Preparation of(4S,10bR)-1,3,4,10b-tetrahydro-4-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 88 withsubstitution of S-tert-butyl 2-amino-3-methylbutanoate hydrochloride forR-tert-butyl 2-aminopropanoate hydrochloride at Step A. MS (ESI) 299(M−Cl).

Example 94 Preparation of(4S,10bS)-1,3,4,10b-tetrahydro-4-(2-methylpropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 88 withsubstitution of S-tert-butyl 2-amino-4-methylpentanoate hydrochloridefor R-tert-butyl 2-aminopropanoate hydrochloride at Step A. MS (ESI) 313(M−Cl).

Example 95 Preparation of(4S,10bR)-1,3,4,10b-tetrahydro-4-(2-methylpropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 88 withsubstitution of S-tert-butyl 2-amino-4-methylpentanoate hydrochloridefor R-tert-butyl 2-aminopropanoate hydrochloride at Step A. MS (ESI) 313(M−Cl).

Example 96 Preparation of(4S,10bS)-1,3,4,10b-tetrahydro-4-(phenylmethyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 88 withsubstitution of S-tert-butyl 2-amino-3-phenylpropanoate hydrochloridefor R-tert-butyl 2-aminopropanoate hydrochloride at Step A. MS (ESI) 347(M−Cl).

Example 97 Preparation of(4S,10bR)-1,3,4,10b-tetrahydro-4-(phenylmethyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 88 withsubstitution of S-tert-butyl 2-amino-3-phenylpropanoate hydrochloridefor R-tert-butyl 2-aminopropanoate hydrochloride at Step A. MS (ESI) 347(M−Cl).

Example 98 Preparation of(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(54 mg, 0.12 mmol) in DME (1.2 μL) was addedtertrakis(triphenylphosphine)palladium(0) (1.7 mg, 0.0015 mmol). After15 min., cis-1-propenylboronic acid (31 mg, 0.37 mmol), potassiumcarbonate (17 mg, 0.12 mmol), and water (0.3 mL) were added. Thereaction was heated to reflux for 3 h and then cooled to room temp. Thereaction was diluted with brine and extracted with EtOAc (3×5 mL). Theorganic layers were combined, dried over Na₂SO₄, and conc. in vacuo to ayellow oil. The oil was purified by flash chromatography (silica gel,0–50% EtOAc in hexanes) to give 42 mg of the desired product as acolorless oil. MS (ESI) 397 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(40 mg, 0.1 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 24 mg of awhite solid. MS (ESI) 297 (M−Cl).

Example 99 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methyl-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 98 withsubstitution of 2-methyl-propenylboronic acid for cis-1-propenylboronicacid at Step A. MS (ESI) 311 (M−Cl).

Example 100 Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methylpropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methylpropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(60 mg, 0.15 mmol) and 10% palladium on carbon (5 mg) in MeOH (2 mL) wasadded hydrogen (1 atm). After 2 h, the reaction was filter and the solidwas washed with methanol. The organic layers were combined and conc. invacuo to a colorless oil. The oil was purified by flash chromatography(silica gel, 0–50% EtOAc in hexanes) to give 28 mg of the desiredproduct as a white solid. MS (ESI) 413 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-(2-methylpropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methylpropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(25 mg, 0.06 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 16 mg of awhite solid. MS (ESI) 313 (M−Cl).

Example 101 Preparation of(R)-1,3,4,10b-tetrahydro-9-methylthio-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methylthio-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(56 mg, 0.13 mmol) in dry DMF (1 mL) at 60° C. was added sodiummethanethiolate (9.9 mg, 0.14 mmol). The reaction was heated to refluxfor 30 min and then cooled to room temperature. The reaction wasquenched with 1M aq. NaOH and extracted with EtOAc (3×5 mL). The organiclayers were combined, dried over Na₂SO₄, and conc. in vacuo to a yellowoil. The oil was purified by flash chromatography (silica gel, 0–33%EtOAc in hexanes) to give 34 mg of the desired product as a colorlessoil. MS (ESI) 403 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-methylthio-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methylthio-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(34 mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to yield 21 mgof a white solid. MS (ESI) 303 (M−Cl).

Example 102 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethylthio7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 101 withsubstitution of sodium ethanethiolate for sodium methanethiolate at StepA. MS (ESI) 317 (M−Cl).

Example 103 Preparation of(R)-1,3,4,10b-tetrahydro-9-isopropylthio-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 101 withsubstitution of sodium 2-propanethiolate for sodium ethanethiolate atStep A. MS (ESI) 331 (M−Cl).

Example 104 Preparation of(R)-1,3,4,10b-tetrahydro-9-butyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 98 withsubstitution of butylboronic acid for cis-1-propenylboronic acid and1,1′-bis(diphenylphosphino)ferrocene palladium(I) dichloridedichloromethane complex for tertrakis(triphenylphosphine)-palladium(0)at Step A. MS (ESI) 313 (M−Cl).

Example 105 Preparation of(R)-1,3,4,10b-tetrahydro-9-(1-cyclohexenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 104 withsubstitution of2-(1-cyclohexenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane acid forbutylboronic acid. MS (ESI) 337 (M−Cl).

Example 106 Preparation of(R)-1,3,4,10b-tetrahydro-9-(3-pentyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(3-pentyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(66 mg, 0.15 mmol) and potassium carbonate (105 mg, 0.76 mmol) in DMF(1.0 mL) was added 1,1′-bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex (12 mg, 0.015 mmol). After 15 min.,0.5 M THF solution of 3-propenylzinc bromide (0.45 mL, 0.9 mmol) wasadded. The reaction was heated to reflux for 15 min and then cooled toroom temp. The reaction was quenched with 1M aq. NaOH and extracted withEtOAc (3×10 mL). The organic layers were combined, dried over Na₂SO₄,and conc. in vacuo to a black oil. The oil was purified by flashchromatography (silica gel, 0–50% EtOAc in hexanes) to give 36 mg of thedesired product as a colorless oil. MS (ESI) 427 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-(3-pentyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(3-pentyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(35 mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 25 mg of awhite solid. MS (ESI) 327 (M−Cl).

Example 107 Preparation of(R)-1,3,4,10b-tetrahydro-9-cyclopentyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 106 withsubstitution of cyclopentylzinc bromide for 3-propenylzinc bromide inStep A. MS (ESI) 325 (M−Cl).

Example 108 Preparation of(R)-1,3,4,10b-tetrahydro-9-(1-cyclohexyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 100 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(1-cyclohexenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one in Step A. MS (ESI) 339 (M−Cl).

Example 109 Preparation of(R)-1,3,4,10b-tetrahydro-9-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 98 withisopropylboronic acid for cis-1-propenylboronic acid in Step A followedby the procedures described in Example 100. MS (ESI) 299 (M−Cl).

Example 110 Preparation of(R)-1,3,4,10b-tetrahydro-9-cyclopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 104 withsubstitution of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor butylboronic acid. MS (ESI) 297 (M−Cl).

Example 111 Preparation of(R)-1,3,4,10b-tetrahydro-9-hydroxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(182 mg, 0.46 mmol) in MeOH (5.0 mL) at −78° C. was bubbled ozone for 5min. until the reaction turned a light blue color. After 5 min., sodiumborohydride (23 mg, 0.6 mmol) was added. The reaction was stir for 1 hrand then warmed to room temp. The reaction was conc. in vacuo to a whitesolid and then dissolved in 1M aq. HCl. After 15 min, the reaction wasdiluted with EtOAc, basefied with NaHCO₃, and treated with di-t-butyldicarbonate (125 mg, 0.58 mmol). After 1 h, the reaction was extractedwith EtOAc (3×5 mL). The organic layers were combined, dried overNa₂SO₄, and conc. in vacuo to a colorless oil. The oil was purified byflash chromatography (silica gel, 0–50% EtOAc in hexanes) to give 141 mgof the desired product as a white solid. MS (ESI) 387 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-hydroxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(14 mg, 0.04 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 10 mg of awhite solid. MS (ESI) 287 (M−Cl).

Example 112 Preparation of(R)-1,3,4,10b-tetrahydro-9-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 100 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)one in Step A. MS (ESI) 271 (M−Cl).

Example 113 Preparation of(R)-1,3,4,10b-tetrahydro-9-methoxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methoxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(30 mg, 0.08 mmol) and proton sponge (26 mg, 0.12 mmol) in dry CH₂Cl₂(1.0 mL) was added trimethyloxonium tetrafluoroborate (11.5 mg, 0.08mmol). The reaction was stir for 16 hr and then quenched with 1M aq.HCl.The reaction was extracted with EtOAc (3×10 mL). The organic layers werecombined, dried over Na₂SO₄, and conc. in vacuo to a pink oil. The oilwas purified by flash chromatography (silica gel, 0–40% EtOAc inhexanes) to yield 13 mg of the desired product as a colorless oil. MS(ESI) 401 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-methoxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methoxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(12 mg, 0.03 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 10 mg of awhite solid. MS (ESI) 301 (M−Cl).

Example 114 Preparation of(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(435 mg, 1.0 mmol), bis(pinacolato)diboron (279 mg, 1.1 mmol), andpotassium acetate (294 mg, 3.0 mmol) in dry DMF (5.0 mL) was addedpalladium(II) acetate (6.7 mg, 0.03 mmol). The reaction was heated to80° C. for 2 h and then cooled to room temp. The reaction was quenchedwith water and extracted with EtOAc (3×5 mL). The organic layers werecombined, dried over Na₂SO₄, and conc. in vacuo to a brown oil. The oilwas dissolved in THF (5 mL) and acetic acid (0.05 mL) and treated withhydrogen peroxide (0.25 mL). The reaction was stirred for 15 min andthen quenched with st. aq. NaHSO₃. The reaction was extracted with EtOAc(3×5 mL). The organic layers were combined, dried over Na₂SO₄, and conc.in vacuo to a brown oil. The oil was purified by flash chromatography(silica gel, 0–70% EtOAc in hexanes) to give 347 mg of the desiredproduct as a pale yellow solid. MS (ESI) 373 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(14 mg, 0.04 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 10 mg of awhite solid. MS (ESI) 273 (M−Cl).

Example 115 Preparation of(R)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(58 mg, 0.16 mmol), and potassium carbonate (33 mg, 0.24 mmol) in dryDMF (1.0 mL) was added methyl iodide (24 mg, 0.17 mmol). The reactionwas stirred for 2 h and then quenched with brine. The reaction wasextracted with EtOAc (3×5 mL). The organic layers were combined, driedover Na₂SO₄, and conc. in vacuo to a pale yellow oil. The oil waspurified by flash chromatography (silica gel, 0–50% EtOAc in hexanes) togive 41 mg of the desired product as a colorless oil. MS (ESI) 387(M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(40 mg, 0.1 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 10 mg of awhite solid. MS (ESI) 287 (M−Cl).

Example 116 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 115 withsubstitution of ethyl iodide for methyl iodide in Step A. MS (ESI) 301(M−Cl).

Example 117 Preparation of(R)-1,3,4,10b-tetrahydro-9-isopropoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 115 withsubstitution of isopropyl iodide for methyl iodide in Step A. MS (ESI)315 (M−Cl).

Example 118 Preparation of(R)-1,3,4,10b-tetrahydro-9-cyclobutylmethoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 115 withsubstitution of cyclobutylmethyl iodide for methyl iodide in Step A. MS(ESI) 341 (M−Cl).

Example 119 Preparation of(R)-1,3,4,10b-tetrahydro-9-isopropoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindolebishydrochloric acid Salt

Prepared according to procedures described in Example 10 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-isopropoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onein Step A. MS (ESI) 315 (M−HCl₂).

Example 120 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethynyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethynyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-trimethylsilylethynyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one,prepared according to procedures described in Example 29 withsubstitution of tributyl(trimethylsilylethynyl)tin for2-(tributylstannyl)furan (44 mg, 0.1 mmol in MeOH (1.0 mL) was addedpotassium carbonate (13 mg, 0.1 mmol). The reaction was stirred for 5min and then quenched with brine. The reaction was extracted with EtOAc(2×5 mL). The organic layers were combined, dried over Na₂SO₄, and conc.in vacuo to a pale yellow oil. The oil was purified by radialchromatography (silica gel, 30% EtOAc in hexanes) to give 27 mg of thedesired-product as a pale yellow oil. MS (ESI) 381 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-ethynyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethynyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(27 mg, 0.8 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 22 mg of awhite solid. MS (ESI) 281 (M−Cl).

Example 121 Preparation of(R)-1,3,4,10b-tetrahydro-9-(trans-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 98 withsubstitution of trans-1-propenylboronic acid for cis-1-propenylboronicacid at Step A. MS (ESI) 297 (M−Cl).

Examples 122 and 123 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation of N,N-diethyl-4-bromo-2-(trifluormethoxy)benzamide

To a stirring solution of 4-bromo-1-iodo-2-(trifluormethoxy)benzene(11600 mg, 32 mmol) in dry THF (300 mL) at −78° C. under Ar was added2.5M n-butyllithium in hexanes (25 mL) dropwise. The reaction wasstirred for 1.5 h and then quenched with crushed dry ice. The reactionwas stirred for 30 min and then slowly wammed to room temperature. Thereaction was partioned between 1 M hydrochloric acid in brine EtOAc. Theorganic layers were separated, washed with sat. aq. NaHSO₃, dried overNa₂SO₄, and conc in vacuo to a brown oil. The oil was dissolved in dryCH₂Cl₂ (300 mL) with dry DMF (0.2 mL) and then treated with oxalylchloride in CH₂Cl₂ (32 mL) dropwise. The reaction was stirred for 4 hand then conc in vacuo to a brown oil. The oil was dissolved in dryCH₂Cl₂ (300 mL) and then treated with diethylamine (5767 mg, 79 mmol)dropwise. The reaction was stirred for 48 h and then conc in vacuo to abrown oil. The oil was purified by flash chromatography (SiO₂, 1:2,EtOAc:hexanes) to yield 8500 mg of the product as a colorless oil. MS(ESI) 341 (M+H).

Step B. Preparation ofN,N-diethyl-4-ethenyl-2-(trifluormethoxy)benzamide

To a stirring degassed solution ofNN-diethyl-4-bromo-2-(trifluormethoxy)benzamide (2373 mg, 7 mmol) in THF(40 mL) was added tetrakis(triphenylphosphine)palladium(0) (97 mg,0.08mmol). After 15 min., potassium carbonate (2898 mg, 21 mmol),2,4,6-trivinylcyclotriboroxane pyridine complex (2663 mg, 7 mmol), andwater (8 mL). The reaction was heated to reflux for 3 h and then cooledto room temperature. The reaction was diluted with brine and extractedwith EtOAc (3×25 mL). The organic layers were combined, dried overNa₂SO₄, and conc. in vacuo to a pale yellow oil. The oil was purified byflash chromatography (SiO₂, 0–50% EtOAc in hexanes) to give 1783 mg ofthe desired product as a colorless oil. MS (ESI) 288 (M+H).

Step C. Preparation of N,N-diethyl-4-ethyl-2-(trifluormethoxy)benzamide

To a stirring degassed solution ofN,N-diethyl-4-ethenyl-2-(trifluormethoxy)benzamide (1783 mg, 6.2 mmol)and 10% palladium on carbon (50 mg) in MeOH (30 mL) was added hydrogen(1 atm). The reaction was stirred for 1 h and then filtered. Thefiltrate was conc. in vacuo to a colorless oil. The oil was purified byflash chromatography (SiO₂, 0–50% EtOAc in hexanes) to give 1489 mg ofthe desired product as a colorless oil. MS (ESI) 290 (M+H).

Step D. Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 1, Steps B–D withsubstitution of N,N-diethyl-4-ethyl-2-(trifluormethoxy)benzamide forN,N-diethyl-2-(trifluormethoxy)benzamide at Step B. Followed byseparation of enatiomers by the procedures described in Example 2 withthe modification of 35% 1:1 MeOH:EtOH for 20% 1:1 MeOH:EtOH. MS (ESI)301 (M−Cl).

Examples 124 and 125 Preparation of(R)-1,3,4,10b-tetrahydro-9-propyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-propyl-7-trifluoromethoxy-pyrazino[2,1-a]soindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 122 withsubstitution of cis-1-propenylboronic acid for2,4,6-trivinylcyclotriboroxane pyridine complex at Step B. MS (ESI) 315(M−Cl).

Examples 126 and 127 Preparation of(R)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation N,N-diethyl-4-hydroxy-2-(trifluormethoxy)benzamide

To a stirring degassed solution ofNN-diethyl-4-bromo-2-(trifluormethoxy)benzamide (2768 mg, 8.2 mmol),bis(pinacolato)diboron (2281 mg, 9.0 mmol), and potassium acetate (2402mg, 24.5 mmol) in dry DMF (60 mL) was added palladium(II) acetate (55mg, 0.25 mmol). The reaction was heated to 80° C. for 2 h and thencooled to room temp. The reaction was quenched with water and extractedwith EtOAc (3×75 mL). The organic layers were combined, dried overNa₂SO₄, and conc. in vacuo to a brown oil. The oil was dissolved in THF(40 mL) and acetic acid (2.0 mL) and treated with hydrogen peroxide (8mL). The reaction was stirred for 15 min and then quenched with st. aq.NaHSO₃. The reaction was extracted with EtOAc (3×40 mL). The organiclayers were combined, dried over Na₂SO₄, and conc. in vacuo to a brownoil. The oil was purified by flash chromatography (silica gel, 20–70%EtOAc in hexanes) to give 1876 mg of the desired product as a whitesolid. MS (ESI) 278 (M+H).

Step B. PreparationN,N-diethyl-4-[(1,1-dimethyethyl)dimethysilyl]oxy-2-(trifluormethoxy)benzamide

To a stirring solution ofN,N-diethyl-4-hydroxy-2-(trifluormethoxy)benzamide (1876 mg, 6.8 mmol)and diisopropylethylamine (1747 mg, 13.5 mmol) in dry DMF (60 mL) wasadded chloro(1,1-dimethylethyl)dimethylsilane (1123 mg, 7.5 mmol). Thereaction was stirred for 16 h and then quenched with 1M HCl. Thereaction was extracted with EtOAc (3×50 mL). The organic layers werecombined, dried over Na₂SO₄, and conc. in vacuo to a pale yellow oil.The oil was purified by flash chromatography (silica gel, 0–40% EtOAc inhexanes) to give 1941 mg of the desired product as a colorless oil. MS(ESI) 392 (M+H).

Step C. PreparationN,N-diethyl-6-carboxaldhyde-4-hydroxy-2-(trifluormethoxy)benzamide

To a stirring solution ofN,N-diethyl-4-[(1,1-dimethyethyl)dimethysilyl]oxy-2-(trifluormethoxy)benzamide(915 mg, 2.3 mmol) and N,N,N′,N′-tetramethylethylenediamine (433 mg, 2.9mmol) in dry THF (6 mL) at −78° C. under Ar was added 1.1 Ms-butyllithium in hexanes (2.66 mL) dropwise. The reaction was stirredfor 30 min and then DMF (0.55 mL) was added. The reaction was stirredfor 15 min and then quenched with methanol (1 mL). After 10 min, thereaction was warmed to room temperature and 1M NaOH was added. After 15min, the reaction was acidified with 1M HCl and extracted with EtOAc(3×15 mL). The organic layers were combined, dried over Na₂SO₄, and concin vacuo to a pale yellow oil. The oil was purified by flashchromatography (SiO2, 0–60% EtOAc in hexanes) to yield 668 mg of thedesired product as a white solid. MS (ESI) 306 (M+H).

Step D. PreparationN,N-diethyl-6-carboxaldhyde-4-methoxy-2-(trifluormethoxy)benzamide

To a stirring solution ofN,N-diethyl-6-carboxaldhyde-4-hydroxy-2-(trifluormethoxy)benzamide (650mg, 2.1 mmol) and potassium carbonate(552 mg, 4 mmol) in dry DMF (20 mL)was added iodomethane (378 mg, 2.66 mmol). The reaction was stirred for16 h and then quenched with water. The reaction was extracted with EtOAc(3×25 mL). The organic layers were combined, dried over Na₂SO₄, and concin vacuo to a yellow oil. The oil was purified by flash chromatography(SiO2, 0–60% EtOAc in hexanes) to yield 675 mg of the desired product asa colorless oil. MS (ESI) 320 (M+H).

Step E. Preparation of(R)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 1, Steps C–D withsubstitution ofN,N-diethyl-6-carboxaldhyde-4-methoxy-2-(trifluormethoxy)benzamide forN,N-diethyl-6-carboxaldhyde-2-(trifluormethoxy)benzamide at Step C.Followed by separation of enatiomers by the procedures described inExample 2 with the modification of 35% 1:1 MeOH:EtOH for 20% 1:1MeOH:EtOH. MS (ESI) 303 (M−Cl).

Examples 128 AND 129 Preparation of(R)-1,3,4,10b-tetrahydro-9-cyclopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-cyclopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. PreparationN-(t-butoxycarbonyl)-(O)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(201 mg, 0.5 mmol) in dry CH₂Cl₂ (3 mL) at −78° C. under Ar was added 1Mboron tribromide in CH₂Cl₂ (1.75 mL). The reaction was stirred for 1 hand then warmed to room temperature for 18 h. The reaction was refluxedfor 24 h and then quenched with water. The reaction was stirred for 30min and then conc. in vacuo to a brown solid. The solid was treated with6M HCl. After 1 h, the reaction was conc. in vacuo to a brown solid. Thesolid was partioned between water and EtOAc, basefied with sodiumbicarbonate, and treated with di-t-butyl dicarbonate (109 mg, 0.5 mmol).The reaction was stirred for 1 h and extracted with EtOAc (3×10 mL). Theorganic layers were combined, dried over MgSO₄, and conc. in vacuo to abrown solid. The solid was purified by triturationwith chloroform toyield 103 mg of the desired product as a white solid. MS (ESI) 389(M+H).

Step B. PreparationN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-trifluormethylsulfonyloxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(100 mg, 0.26 mmol) and 2,6-lutidine (139 mg, 1.3 mmol) in dry CH₂Cl₂ (3mL) at 0° C. was added trifluormethanesulfonic anhydride (109 mg, 0.39mmol). The reaction was stirred for 30 min and then quenched withmethanol. The reaction was conc. in vacuo to a brown oil. The oil waspurified by flash chromatography (SiO2, 0–50% EtOAc in hexanes) to yield101 mg of the desired product as a white solid. MS (ESI) 521 (M+H).

Step C. PreparationN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-cyclopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-trifluormethylsulfonyloxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(100 mg, 0.19 mmol),2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101 mg, 0.6mmol), and potassium carbonate (138 mg, 1.0 mmol) in DME (2 mL) under Arwas added bis(diphenylphosphino)ferrocene palladium(II) dichloridedichloromethane complex (5 mg, 0.006 mmol) and water (0.2 mL). Thereaction was heated to reflux for 3 h and then cooled to roomtemperature. The reaction was quenched with 1M NaOH and extracted withEtOAc (3×5 mL). The organic layers were combined, dried over Na₂SO₄, andconc in vacuo to a brown oil. The oil was purified by flashchromatography (SiO2, 0–50% EtOAc in hexanes) to yield 70 mg of thedesired product as a white solid. MS (ESI) 413 (M+H).

Step D. Preparation of(R)-1,3,4,10b-tetrahydro-9-cyclopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-cyclopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

The compounds were separated by chiral HPLC using an OD column with 65%heptane with 0.1% diethylamine and 35% 1:1 MeOH:EtOH with 0.1%diethylamine to yield 25 mg of the R enantiomer and 24 mg of the Senantiomer as white solids. The solids were individually dissolved indry ether (1 mL)and the treated with hydrochloric acid (1 mL). Thereaction was stirred for 1 h and then conc. in vacuo to a white solid.The solid was dissolved in water and lyophilized to yield 20 mg of the Renantiomer and 20 mg of the S enantiomer as white solids. MS (ESI) 313(M−Cl).

Examples 130 and 131 Preparation of(R)-1,3,4,10b-tetrahydro-9-isopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-isopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. PreparationN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-isopropenyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-trifluormethylsulfonyloxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(111 mg, 0.21 mmol), isopropenylboronic acid (55 mg, 0.64 mmol), andpotassium carbonate (145 mg, 1.1 mmol) in DME (2 mL) under Ar was addedtertrakis(triphenylphosphine)-palladium(0) (7 mg, 0.006 mmol) and water(0.2 mL). The reaction was heated to reflux for 3 h and then cooled toroom temperature. The reaction was quenched with 1M NaOH and extractedwith EtOAc (3×5 mL). The organic layers were combined, dried overNa₂SO₄, and conc in vacuo to a brown oil. The oil was purified by flashchromatography (SiO2, 0–50% EtOAc in hexanes) to yield 68 mg of thedesired product as a colorless oil. MS (ESI) 413 (M+H).

Step B. PreparationN-(t-butoxycarbonyl)-(O)-1,3,4,10b-tetrahydro-9-isopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-isopropenyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(67 mg, 0.16 mmol) and 10% palladium on carbon (5 mg) in MeOH (3 mL) wasadded hydrogen (1 atm). The reaction was stirred for 2 h and thenfiltered. The filtrate was conc in vacuo to a colorless oil. The oil waspurified by flash chromatography (SiO2, 0–50% EtOAc in hexanes) to yield67 mg of the desired product as a colorless oil. MS (ESI) 415 (M+H).

Step C. Preparation of(R)-1,3,4,10b-tetrahydro-9-isopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-isopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

The compounds were separated by chiral HPLC using an OD column with 65%heptane with 0.1% diethylamine and 35% 1:1 MeOH:EtOH with 0.1%diethylamine to yield 29 mg of the R enantiomer and 27 mg of the Senantiomer as colorless oils. The oils were individually dissolved indry ether (1 mL)and the treated with hydrochloric acid (1 mL). Thereaction was stirred for 1 h and then conc. in vacuo to a white solid.The solid was dissolved in water and lyophilized to yield 18 mg of the Renantiomer and 17 mg of the S enantiomer as white solids. MS (ESI) 315(M−Cl).

Example 132 Preparation of a Mixture of Preparation of a Mixture of(1S,2R,10bR)-1,3,4,10b-tetrahydro-9-(2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,2S,10bR)-1,3,4,10b-tetrahydro-9-(2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation of a Mixture ofN-(t-butoxycarbonyl)-(1S,2R,10bR)-1,3,4,10b-tetrahydro-9-(2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt andN-(t-butoxycarbonyl)-(1R,2S,10bR)-1,3,4,10b-tetrahydro-9-(2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(75 mg, 0.19 mmol) and palladium(II) acetate (1 mg, 0.004 mmol) inCH₂Cl₂ (1 mL) under Ar was added a 0.5M solution of diazomethane inether (2.6 mL). After 1 h, the reaction was warmed to room temperaturefor 16 h. The addition of diazomethane was repeated twice more. Thereaction was filtered and then conc. in vacuo to a pale yellow oil. Theoil was dissolved in acetone (2 mL) and treated with 4-methylmorpholineN-oxide (26 mg, 0.22 mmole) and osmium tetraoxide in water (1.0 mg in0.16 mL). The reaction was stirred for 1 h and then quenched with sat.aq. Na₂SO₃. The reaction was extracted with EtOAc (3×10 mL). The organiclayers were combined, dried over MgSO₄, and conc in vacuo to a paleyellow oil. The oil was purified by flash chromatography (SiO2, 0–50%EtOAc in hexanes) to yield 28 mg of the desired product as a colorlessoil. MS (ESI) 411 (M+H).

Step B. Preparation of a Mixture of(1S,2R,10bR)-1,3,4,10b-tetrahydro-9-(2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,2S,10bR)-1,3,4,10b-tetrahydro-9-(2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

To a stirring solution ofN-(t-butoxycarbonyl)-(10bR)-1,3,4,10b-tetrahydro-9-[(1S,2R)-2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneandN-(t-butoxycarbonyl)-(10bR)-1,3,4,10b-tetrahydro-9-[(1R,2S)-2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(22 mg, 0.05 mmol) in dry ether (2 mL) was added hydrochloric acid (1mL). The reaction was stirred for 1 h and then conc. in vacuo to a whitesolid. The solid was dissolved in water and lyophilized to 15 mg of awhite solid. MS (ESI) 311 (M−Cl).

Example 133 Preparation of a Mixture of(1S,2S,10bR)-1,3,4,10b-tetrahydro-9-(2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,2R,10bR)-1,3,4,10b-tetrahydro-9-(2-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 132 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(trans-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneat Step A. MS (ESI) 311 (M−Cl).

Example 134 Preparation of a Mixture of(R)-1,3,4,10b-tetrahydro-9-(1-methylcyclopropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 132 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(isopropenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneat Step A. MS (ESI) 311 (M−Cl).

Examples 135 and 136 Preparation of(R)-1,3,4,10b-tetrahydro-9-difluoromethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-difluoromethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Step A. Preparation ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-carboxaldhyde-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-vinyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(408 mg, 1.1 mmol) in MeOH (5.0 mL) at −78° C. was bubbled ozone for 5min. until the reaction turned a light blue color. After 5 min.,nitrogen was bubbled thru the reaction for 5 min and thentriphenylphosphine (308 mg, 1.2 mmol) was added. After 15 min, thereaction was conc. in vacuo to a yellow oil. The oil was purified byflash chromatography (SiO2, 0–50% EtOAc in hexanes) to yield 321 mg ofthe desired product as a white solid. MS (ESI) 383 (M+H).

Step B. Preparation ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-difluoromethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-carboxaldehyde-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(124 mg, 0.32 mmol) in CH₂Cl₂ (3.0 mL) at −78° C. in a teflon vial wasadded [bis(2-methoxyethyl)amino]sulfur trifluoride (122 mg, 0.55 mmol).After 30 min, the reaction was warmed to room temperature for 30 min.The reaction was quenched with sat aq NaHCO₃. The reaction was extractedwith CH₂C₁₂ (3×5 mL). The organic layers were combined, dried overNa₂SO₄, and conc in vacuo to a yellow oil. The oil was purified by flashchromatography (SiO2, 0–50% EtOAc in hexanes) to yield 121 mg of thedesired product as a colorless oil. MS (ESI) 407 (M+H).

Step C. Preparation of(R)-1,3,4,10b-tetrahydro-9-difluoromethyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-difluoromethyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Examples 130 and 131 atStep C. MS (ESI) 307 (M−Cl).

Examples 137 and 138 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7-chloro-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Step A. Preparation of N,N-diethyl-4-bromo-2-chlorobenzamide

Prepared according to procedures described in Example 1 withsubstitution of 4-bromo-2-chlorobenzoic acid for2-trifluoromethoxybenzoic acid at Step A. MS (ESI) 290 (M+H).

Step B. Preparation of N,N-diethyl-2-chloro-4-ethenylbenzamide

Prepared according to procedures described in Example 122 Step B withsubstitution of N,N-diethyl-4-bromo-2-chlorobenzamide forN,N-diethyl-4-bromo-2-trifluoromethoxybenzamide. MS (ESI) 238 (M+H).

Step C. Preparation of N,N-diethyl-2-chloro-4-ethylbenzamide

Prepared according to procedures described in Example 100 Step A. MS(ESI) 240 (M−Cl).

Step D. Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7-chloro-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 43 withsubstitution of N,N-diethyl-2-chloro-4-ethylbenzamide forN,N-diethyl-2-chlorobenzamide at Step A followed by the separation ofenantiomers according to the procedures described in Example 128 Step D.MS (ESI) 251 (M−Cl).

Examples 139 and 140 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-propyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7-chloro-9-propyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 137 withsubstitution of 1-cis-propenylboronic acid for2,4,6-trivinylcyclotriboroxane pyridine complex at Step B. MS (ESI) 265(M−Cl).

Examples 141 and 142 Preparation of(R)-1,3,4,10b-tetrahydro-7-methylthio-9-propyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7-methylthio-9-propyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Step A. Preparation N,N-diethyl-2-methylthio-4-propylbenzainide

To a stirring solution of N,N-diethyl-4-propylbenzamide (2.0 g, 9.3mmol) and N,N,N′,N′-tetramethylethylenediamine (1085 mg, 9.4 mmol) indry THF (93 mL) at −78° C. under Ar was added 0.78 M s-butyllithium inhexanes (12 mL). The reaction was stirred for 30 min and then methyldisulfide (1936 mg, 12.1 mmol) was added. The reaction was stirred for 5min and then quenched with MeOH (1 mL) and brine. The reaction wasextracted with EtOAc (3×50 mL). The organic layers were combined, driedover Na₂SO₄, and conc in vacuo to a yellow oil. The oil was purified byflash chromatography (SiO2, 0–30% EtOAc in hexanes) to yield 2.1 g (86%)of the product as a yellow oil. MS (ESI) 266 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-7-methylthio-9-propyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7-methylthio-9-propyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 43 withsubstitution of N,N-diethyl-2-methylthio-4-propylbenzamide forN,N-diethyl-2-chlorobenzamide at Step A followed by the separation ofenantiomers according to the procedures described in Example 128 Step D.MS (ESI) 277 (M−Cl).

Examples 143 and 144 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methylthio-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-methylthio-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 141 withsubstitution of N,N-diethyl-4-ethylbenzamide forN,N-diethyl-4-propylbenzamide at Step A. MS (ESI) 263 (M−Cl).

Examples 145 and 146 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-isopropylthio-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-methylthio-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 141 withsubstitution of N,N-diethyl-4-ethylbenzamide forN,N-diethyl-4-propylbenzamide and isopropyl disulfide for methyldisulfide at Step A. MS (ESI) 291 (M−Cl).

Examples 147 AND 148 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-ethylthio-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-ethylthio-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 141 withsubstitution of N N-diethyl-4-ethylbenzamide for NN-diethyl-4-propylbenzamide and ethyl disulfide for methyl disulfide atStep A. MS (ESI) 277 (M−Cl).

Example 149 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methylsulfonyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Step A. PreparationN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methylsulfonyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methylthio-pyrazino[2,1-a]isoindol-6(2H)-one(42 mg, 0.12 mmol) in dry MeOH (0.75 mL) and water (0.75 mL) was addedoxone (93 mg, 0.15 mmol). The reaction was stirred for 4 h and thendiluted with water. The reaction was extracted with EtOAc (3×5 mL). Theorganic layers were combined, dried over Na₂SO₄, and conc in vacuo to ayellow oil. The oil was purified by flash chromatography (SiO2, 0–50%EtOAc in hexanes) to yield 38 mg (84%) of the product as a colorlessoil. MS (ESI) 395 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methylsulfonyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 10 in StepB. MS(ESI) 295 (M−Cl).

Example 150 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 128 Step A withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one,produced by procedures described in example 126 eith the substitution ofN,N-diethyl-4-bromo-2-chlorobenzamide forN,N-diethyl-4-bromo-2-trifluoromethoxybenzamide, forN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one.Followed by the separation of enantiomers according to the proceduresdescribed in Example 128 Step D. MS (ESI) 239 (M−Cl).

Example 151 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-cyclopropyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 128 Steps B–D withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(O)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onein Step B. MS (ESI) 263 (M−Cl).

Example 152 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-ethenyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 151 withsubstitution of 2,4,6-trivinylcyclotriboroxane pyridine complex for2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step B. MS(ESI) 249 (M−Cl).

Example 153 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-methyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 151 withsubstitution of 2,4,6-trimethylcyclotriboroxane pyridine complex for2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step B. MS(ESI) 237 (M−Cl).

Example 154 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-isopropyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 130 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-9-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-onein Step A. MS (ESI) 265 (M−Cl).

Example 155 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-ethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 115 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one forN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneand ethyl iodide for methyl iodide in Step A. MS (ESI) 267 (M−Cl).

Example 156 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-cyclobutylmethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 115 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneand cyclobutylmethyl iodide for methyl iodide in Step A. MS (ESI) 307(M−Cl).

Example 157 Preparation of(R)-1,3,4,10b-tetrahydro-7-chloro-9-cyclopropylmethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 115 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one forN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneand cyclopropylmethyl iodide for methyl iodide in Step A. MS (ESI) 293(M−Cl).

Examples 158 and 159 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Step A. Preparation of N,N-diethyl-4-chloro-2-methoxybenzamide

Prepared according to procedures described in Example 1 Step A withsubstitution of 4-chloro-2-methoxybenzoic acid for2-trifluoromethoxybenzoic acid. MS (ESI) 290 (M+H).

Step B. Preparation of N,N-diethyl-4-ethenyl-2-methoxybenzamide

To a stirring degassed solution ofN,N-diethyl-4-chloro-2-methoxybenzamide (65 mg, 0.35 mmol), potassiumfluoride (134 mg, 2.3 mmol), and 2,4,6-trivinylcyclotriboroxane pyridinecomplex (132 mg, 0.35 mmol) in 1,4-dioxane (3 mL) was addedbis(tri-t-butylphosphine)palladium (5 mg,0.01 mmol). The reaction washeated to reflux for 5 h and then cooled to room temperature. Thereaction was diluted with brine and extracted with EtOAc (3×5 mL). Theorganic layers were combined, dried over Na₂SO₄, and conc. in vacuo to apale yellow oil. The oil was purified by flash chromatography (SiO₂,0–50% EtOAc in hexanes) to give 40 mg of the desired product as acolorless oil. MS (ESI) 234 (M+H).

Step C. Preparation of N,N-diethyl-4-ethyl-2-methoxybenzamide

Prepared according to procedures described in Example 100 at Step A. MS(ESI) 240 (M−Cl).

Step D. Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 1 Steps B–D withsubstitution of N,N-diethyl-4-ethyl-2-methoxybenzamide forN,N-diethyl-2-trifluoromethoxybenzamide at Step B followed by theseparation of enantiomers according to the procedures described inExample 2 with the modification of 35% 1:1 MeOH:EtOH for 20% 1:1MeOH:EtOH. MS (ESI) 247 (M−Cl).

Examples 161 and 162 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 128 Step A withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one.Followed by the separation of enantiomers according to the proceduresdescribed in Example 128 Step D. MS (ESI) 233 (M−Cl).

Examples 163 and 164 Preparation of(R)-1,3,4,10b-tetrahydro-7-ethoxy-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7-ethoxy-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 115 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethyl-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one forN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneand ethyl iodide for methyl iodide in Step A. Followed by the separationof enantiomers according to the procedures described in Example 128 StepD. MS (ESI) 261 (M−Cl).

Examples 165 and 166 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-isopropoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-isopropoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 115 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethyl-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one forN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneand isopropyl iodide for methyl iodide in Step A. Followed by theseparation of enantiomers according to the procedures described inExample 128 Step D. MS (ESI) 261 (M−Cl).

Examples 167 and 168 Preparation of(R)-1,3,4,10b-tetrahydro-7-cyclopropyl-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7-cyclopropyl-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 128 Steps B–D withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-ethyl-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-onefor N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onein Step B. MS (ESI) 257 (M−Cl).

Examples 169 and 170 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-methyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 167 withsubstitution of 2,4,6-trimethylcyclotriboroxane pyridine complex for2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step B. MS(ESI) 237 (M−Cl).

Examples 171 and 172 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-isopropyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-isopropyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 130 withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-9-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-onein Step A. MS (ESI) 259 (M−Cl).

Examples 173 and 174 Preparation of(R)-1,3,4,10b-tetrahydro-7,9-diethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7,9-diethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 130 withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-9-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneand 2,4,6-trivinylcyclotriboroxane pyridine complex for isopropenylboronic acid in Step A. MS (ESI) 245 (M−Cl).

Examples 175 AND 176 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-propyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-propyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 130 withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-9-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneand 1-cispropenylboronic acid for isopropenyl boronic acid in Step A. MS(ESI) 259 (M−Cl).

Examples 177 and 178 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-(2-methylpropyl)-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-(2-methylpropyl)-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 130 withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-9-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneand 2,2-dimethylethenylboronic acid for isopropenyl boronic acid in StepA. MS (ESI) 273 (M−Cl).

Examples 179 and 180 Preparation of(R)-1,3,4,10b-tetrahydro-7-cyclopentyl-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7-cyclopentyl-9-ethyl-(2-methylpropyl)-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 130 withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-9-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneand 1-cyclopentenylboronic acid for isopropenyl boronic acid in Step A.MS (ESI) 285 (M−Cl).

Examples 181 and 182 Preparation of(R)-1,3,4,10b-tetrahydro-7-cyclohexyl-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-7-cyclohexyl-9-ethyl-(2-methylpropyl)-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 130 withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-9-trifluoromethylsulfonyloxy-pyrazino[2,1-a]isoindol-6(2H)-oneand 1-cyclohexenylboronic acid for isopropenyl boronic acid in Step A.MS (ESI) 298 (M−Cl).

Examples 183 and 184 Preparation of(R)-1,3,4,10b-tetrahydro-9-ethyl-7-hydroxymethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid and(S)-1,3,4,10b-tetrahydro-9-ethyl-7-hydroxymethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid

Prepared according to procedures described in Example 111 Step A withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-ethenyl-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one.Followed by the separation of enantiomers according to the proceduresdescribed in Example 128 Step D. MS (ESI) 247 (M−Cl).

Examples 185 and 186 Preparation of(R)-1,3,4,10b-tetrahydro-9-chloro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-chloro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. PreparationN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-chloro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring degassed solution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(464 mg, 1.1 mmol) in dry DMF (5 mL) was added copper(I) chloride (211mg, 2.1 mmol). The reaction was heated to reflux for 4 h and then cooledto room temp. The reaction was treated with di-t-butyl dicarbonate (350mg, 1.6 mmol). The reaction was stirred for 1 h ann then quenched with9:1 sat. NH4Cl:NH4OH. After 15 min., the reaction was extracted withEtOAc (3×10 mL). The organic layers were combined, dried over Na₂SO₄,and conc. in vacuo to a brown oil. The oil was purified by flashchromatography (silica gel, 0–50% EtOAc in hexanes) to yield 140 mg ofthe desired product as a colorless oil. MS (ESI) 391 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-9-chloro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-9-chloro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 128 Step D withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-chloro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-cyclopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 291 (M−Cl).

Example 187 Preparation of(R)-1,3,4,10b-tetrahydro-8-bromo-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 11 withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one forN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 351 (M−Cl).

Examples 188 and 189 Preparation of(R)-1,3,4,10b-tetrahydro-7,9-ditrifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-7,9-ditrifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 43 withsubstitution of 2,4-ditrifluoromethylbenzoic acid for 2-chlorobenzoicacid followed by separation of enantiomers according to the proceduresdescribed in example 2 with substitution of AD column with 85% heptanewith 0.1% diethylamine and 15% 1:1 MeOH:EtOH with 0.1% diethylamine forOD column with 80% heptane with 0.1% diethylamine and 20% 1:1 MeOH:EtOHwith 0.1% diethylamine. MS (ESI) 325 (M−Cl).

Examples 190 and 191 Preparation of(R)-1,3,4,10b-tetrahydro-10-chloro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-10-chloro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 43 withsubstitution of 5-chloro-2-methoxybenzoic acid for 2-chlorobenzoic acidfollowed by separation of enantiomers according to the proceduresdescribed in example 2. MS (ESI) 253 (M−Cl).

Examples 192 and 193 Preparation of(R)-1,3,4,10b-tetrahydro-7,8-dichloro-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-7,8-dichloro-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 43 withsubstitution of 2,3-dichlorobenzoic acid for 2-chlorobenzoic acidfollowed by separation of enantiomers according to the proceduresdescribed in example 2. MS (ESI) 257 (M−Cl).

Examples 194 and 195 Preparation of(R)-1,3,4,10b-tetrahydro-8-chloro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-8-chloro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation NN-diethyl-3-chloro-2-hydroxybenzamide

To a stirring solution of 3-chloro-2-hydroxybenzoic acid(7.2 g, 42 mmol)and diethyl amine (15.2 g, 209 mmol) in dry CH₂Cl₂ (200 mL) was addedbenzotriazol-1-yloxy tripyrrolidinophosphonium hexafluorophosphate (22.8g, 44 mmol) in dry CH₂Cl₂ (200 mL). The reaction was stirred overnightand then quenched with 6M HCl. The layers were separated and the aqueouslayer was extracted with EtOAc (3×100 mL). The organic layers werecombined, dried over Na₂SO₄, and conc. in vacuo to a brown oil. The oilwas purified by flash chromatography (silica gel, 0–50% EtOAc irihexanes) to yield 7.6 g of the desired product as a reddish oil. MS(ESI) 228 (M+H).

Step B. Preparation of N,N-diethyl-3-chloro-2-methoxybenzamide

Prepared according to procedures described in Example 115 Step A withsubstitution of N,N-diethyl-3-chloro-2-hydroxybenzamide forN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 242 (M+H).

Step C. Preparation of(R)-1,3,4,10b-tetrahydro-8-chloro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-8-chloro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 43 withsubstitution of N,N-diethyl-3-chloro-2-methoxybenzamide forN,N-diethyl-2-chlorobenzamide followed by separation of enantiomersaccording to the procedures described in example 2. MS (ESI) 253 (M−Cl).

Examples 196 and 197 Preparation of(R)-1,3,4,10b-tetrahydro-8-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-8-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. PreparationN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-8-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 158 Step B–C withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-8-chloro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onefor N,N-diethyl-4-chloro-2-methoxybenzamide in Step B. MS (ESI) 347(M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-8-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-8-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 128 Step D withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-8-ethyl-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-cyclopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 247 (M−Cl).

Example 198 Preparation of(R)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 100 withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-8-chloro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one forN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onein Step A. MS (ESI) 219 (M−Cl).

Example 199 Preparation of(S)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 100 withsubstitution ofN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-8-chloro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one forN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onein Step A. MS (ESI) 219 (M−Cl).

Example 200 Preparation of(R)-1,3,4,10b-tetrahydro-7-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. PreparationN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-ethenyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to procedures described in Example 158 Step B withsubstitution ofN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-one for N,N-diethyl-4-chloro-2-methoxybenzamide in.MS (ESI) 315 (M+H).

Step B. Preparation(R)-1,3,4,10b-tetrahydro-7-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 100 withsubstitution ofN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-ethenyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onein Step A. MS (ESI) 217 (M−Cl).

Examples 201 and 202 Preparation of(R)-1,3,4,10b-tetrahydro-7-cyclopropyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-7-cyclopropyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 128 withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onein Step A. MS (ESI) 229 (M−Cl).

Examples 203 and 204 Preparation of(R)-1,3,4,10b-tetrahydro-7-cyclopentyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-7-cyclopentyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 128 withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-methoxy-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-onein Step A. MS (ESI) 257 (M−Cl).

Examples 205 and 206 Preparation of(R)-1,3,4,10b-tetrahydro-10b-methyl7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-10b-methyl7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. PreparationN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-10b-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a stirring solution ofN-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(150 mg, 0.4 mmol) and methyl iodide (125 mg, 0.9 mmol) in dry DMF (6mL) was added sodium hydride (15 mg, 0.6 mmol). The reaction was stirredfor 3 h and then quenched with brine. The reactionwas extracted withEtOAc (3×10 mL). The organic layers were combined, dried over Na₂SO₄,and conc. in vacuo to a brown oil. The oil was purified by flashchromatography (silica gel, 0–50% EtOAc in hexanes) to yield 59 mg ofthe desired product as a white solid. MS (ESI) 371 (M+H).

Step B. Preparation of(R)-1,3,4,10b-tetrahydro-10b-methyl7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(S)-1,3,4,10b-tetrahydro-10b-methyl7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to procedures described in Example 128 Step D withsubstitution ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-10b-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-cyclopropyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 271 (M−Cl).

Example 207 Preparation of(3R,11aR)-1,2,3,4,11,11a-Hexahydro-3-methyl-pyrazino[1,2-b]isoquinolin-6-one

Step A. Preparation of[N-(tert-butyloxycarbonyl)-R-phenylalanyl]-N-(benzyl)-R-alanine, methylester

To a stirring solution of (R)-N-(tert-butyloxycarbonyl)-phenylalanine(0.50 g, 1.9 mmol) in dry CH₂Cl₂ (10 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (0.50 g, 3.2mmol) and 1-hydroxybenzotriazole hydrate (0.28 g, 2.2 mmol). Thereaction was stirred at ambient temperature for 30 min and thenN-benzyl-(D)-alanine, methyl ester hydrochloride (0.53 g, 2.3 mmol) andtriethylamine (0.34 ml, 2.4 mmol) were added. After stirring at ambienttemperature overnight and then at 50° C. for one hour, the reaction wastransferred to a separatory funnel with CH₂Cl₂. Extraction with CH₂Cl₂and washing of the organic layer with water, saturated NaHCO₃, and brineand drying with MgSO₄ afforded 1.0 g of crude product after evaporationof the solvent. Purification by flash chromatography (SiO₂, hexanes to30% EtOAc in hexanes) afforded pure product (0.34 g, 41% yield). MS(ESI) 441 (M+H).

Step B. Preparation of (3R,6R)-1,3-Dibenzyl-6-methylpiperazine-2,5-dione

A solution of[N-(tert-butyloxycarbonyl)-R-phenylalanyl]-N-(benzyl)-R-alanine, methylester (0.22 g, 0.50 mmol) in EtOAc (5 ml) was cooled to 0° C. GaseousHCl was slowly bubbled through the solution for 10 min and then the icebath was removed and the reaction allowed to stir at ambient temperaturefor 1 h. The reaction mixture was evaporated in vacuo and the residuetransferred to a separatory funnel with CH₂Cl₂. Washing the organiclayer with saturated NaHCO₃, and brine and drying with MgSO₄ affordedproduct (0.15 g, 100% yield) after evaporation of the solvent. MS (ESI)309 (M+H). This was used in the next step without further purification.

Step C. Preparation of (2R,5R)-1,5-Dibenzyl-2-methylpiperazine

Lithium aluminum hydride (1 M in THF, 4.2 ml, 4.2 mmol) was addeddropwise over 15 min to a solution of(3R,6R)-1,3-dibenzyl-6-methylpiperazine-2,5-dione (0.30 g, 0.98 mmol) inTHF (6.0 ml) stirring at 0° C. After stirring at 65° C. for 19 h, thereaction was allowed to cool to room temperature and was slowly quenchedwith water (0.40 ml). Sodium hydroxide (1 N, 0.8 ml) and then water(0.60 ml) were added and the gelatinous solid was filtered rinsing withTHF. The filtrate was evaporated in vacuo and the residue wastransferred to a separatory funnel with EtOAc. Washing the organic layerwith brine and drying with MgSO₄ afforded product (0.28 g) afterevaporation of the solvent. This was used in the next step withoutfurther purification.

Step D. Preparation of (2R,5R)-Methyl2,4-dibenzyl-5-methylpiperazine-1-carboxylate

Pyridine (0.3 mL, 3.7 mmol) was added to a stirring solution of(2R,5R)-1,5-dibenzyl-2-methylpiperazine (0.28 g, 1.0 mmol) and methylchloroformate (0.10 g, 0.087 ml, 1.1 mmol) in CH₂Cl₂ (11 ml). Afterstirring at ambient temperature for 1 day, the reaction was evaporatedin vacuo and the residue purified by flash chromatography (SiO₂, 5% MeOHin CH₂Cl₂) to afford pure product (0.17 g, 49% yield over the twosteps). MS (ESI) 339 (M+H).

Step E. Preparation of(3R,11aR)-1,2,3,4,11,11a-Hexahydro-2-benzyl-3-methyl-pyrazino[1,2-b]isoquinolin-6-one

A mixture of (2R,5R)-methyl2,4-dibenzyl-5-methylpiperazine-1-carboxylate (0.17 g, 0.5 mmol),phosphorous oxychloride (3 ml) and phosphorous pentoxide (0.28 g, 1.0mmol) was stirred at 100° C. under nitrogen overnight. The reaction wasremoved from the heat, quenched with ice, and brought to pH 8 withsaturated NaHCO₃. Extraction with ethyl acetate (2×) and washing thecombined organic layers with brine and drying over MgSO₄ afforded 0.13 gof crude product after evaporation of the solvent.

Flash chromatography (SiO₂, 4% MeOH in CH₂Cl₂) afforded pure product (81mg, 53% yield). MS (ESI) 307 (M+H).

Step F. Preparation of(3R,11aR)-1,2,3,4,11,11a-Hexahydro-3-methyl-pyrazino[1,2-b]isoquinolin-6-one

(3R,11aR)-1,2,3,4,11,11a-Hexahydro-2-benzyl-3-methyl-pyrazino[1,2-b]isoquinolin-6-one(81 mg, 0.26 mmol) and 10% palladium on carbon (25 mg) in methanol (6.5ml) was stirred under a balloon of hydrogen for 19 h. Evapoaration ofthe filtrate after filtration through Celite® afforded pure(3R,11aR)-1,2,3,4,11,11a-hexahydro-3-methyl-pyrazino[1,2-b]isoquinolin-6-one(56 mg, 83% yield). MS (ESI) 217 (M+H).

Example 208 Preparation of(11R,11aR)-1,2,3,4,11,11a-Hexahydro-11-methyl-pyrazino[1,2-b]isoquinolin-6-one

The title compound was prepared according to procedures described inExample 207 from(D)-N-(tert-butyloxycarbonyl)-erythro-β-methylphenylalanine (ARCOS) andN-benzyl glycine, ethyl ester (Aldrich). Final isolation from flashchromatography (SiO₂, 10% 1 N ammonia in MeOHICH₂Cl₂) afforded(11R,11aR)-1,2,3,4,11,11a-hexahydro-11-methyl-pyrazino[1,2-b]isoquinolin-6-one[MS (ESI) 217 (M+H)].

Example 209 Preparation of(11aR)-1,2,3,4,11,11a-Hexahydro-11a-methyl-pyrazino[1,2-b]isoquinolin-6-one

Step A. Preparation of[N-(tert-butyloxycarbonyl)-α-methyl-(R)-phenylalanyl]-glycine, ethylester

To a stirring solution of(R)-N-(tert-butyloxycarbonyl)-α-methylphenylalanine (0.72 g, 2.6 mmol)in dry CH₂Cl₂ (16 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.69 g,4.4 mmol) and 1-hydroxybenzotriazole hydrate (0.39 g, 2.9 mmol). Thereaction was stirred at ambient temperature for 30 min and then glycine,ethyl ester hydrochloride (0.62 g, 5.2 mmol) and triethylamine (0.85 ml,5.7 mmol) were added. After stirring at ambient temperature for 3 h, thereaction was transferred to a separatory funnel with CH₂Cl₂. Extractionwith CH₂Cl₂ and washing of the organic layer with water, saturatedNaHCO₃, and brine and drying with MgSO₄ afforded 0.94 g of crude productafter evaporation of the solvent. Purification by flash chromatography(SiO₂, 0.2 to 10% MeOH in CH₂Cl₂) afforded pure product (0.87 g, 93%yield). MS (ESI) 365 (M+H).

Step B. Preparation of (α-methyl-(R)-phenylalanyl)glycine, ethyl ester

[N-(tert-butyloxycarbonyl)-α-methyl-(R)-phenylalanyl]glycine, ethylester was stirred at ambient temperature in 4N HCl in dioxane (30 ml).After 1.5 h, the solvent was removed in vacuo. The residue wastransferred to a separatory funnel with EtOAc. Extraction with EtOAc(2×) and washing of the combined organic layers brine and drying withMgSO₄ afforded 0.63 g of crude product after evaporation of the solvent.This was used in the next step without further purification. MS (ESI)265 (M+H).

Step C. Preparation of (R)-3-Benzyl-3-methylpiperazine-2,5-dione

A solution of α-methyl-(R)-phenylalanyl)glycine, ethyl ester (0.63 g,2.4 mmol) in sec-butanol (14 ml) and toluene (7 ml) was stirred atreflux. After 21 h, the solvent was removed in vacuo and the residueazeotroped with toluene (3×) to afford the product (0.51 g, 100% yield)as a white solid. MS (ESI) 219 (M+H). This was used in the next stepwithout further purification.

Step D. Preparation of (R)-2-Benzyl-2-methylpiperazine

Lithium aluminum hydride (1 M in THF, 7.2 ml, 7.2 mmol) was addeddropwise over 15 min to a solution of(R)-3-benzyl-3-methylpiperazine-2,5-dione (0.51 g, 2.4 mmol) in THF (20ml) stirring at ambient temperature. After stirring at reflux for 6 h,the reaction was allowed to cool to room temperature and was slowlyquenched with water (0.27 ml). Sodium hydroxide (1 N, 1.0 ml) and thenwater (0.10 ml) were added and the gelatinous solid was filtered rinsingwith THF. The filtrate was evaporated in vacuo and the residue wastransferred to a separatory funnel with EtOAc. Washing the organic layerwith brine and drying with MgSO₄ afforded product (0.38 g) afterevaporation of the solvent. This was used in the next step withoutfurther purification. MS (ESI) 191 (M+H).

Step E. Preparation of (R)-Dimethyl2-benzyl-2-methylpiperazine-1,4-dicarboxylate

Diethylisopropylamine (0.98 ml, 5.0 mmol) was added to a stirringsolution of (R)-2-benzyl-2-methylpiperazine (0.38 g, 2.0 mmol) andmethyl chloroformate (0.41 g, 0.35 ml, 2.8 mmol) in CH₂Cl₂ (20 ml).After stirring at ambient temperature for 2 h, the reaction wasevaporated in vacuo and the residue purified by flash chromatography(SiO₂, CH₂Cl₂ to 40% EtOAc in CH₂Cl₂) to afford pure product (0.28 g,34% yield over the two steps). MS (ESI) 307 (M+H).

Step F. Preparation of(11aR)-1,2,3,4,11,11a-Hexahydro-11a-methyl-pyrazino[1,2-b]isoquinolin-6-one

A mixture of (R)-dimethyl 2-benzyl-2-methylpiperazine-1,4-dicarboxylate(0.28 g, 0.91 mmol), phosphorous oxychloride (5.9 ml) and phosphorouspentoxide (0.57 g, 1.8 mmol) was stirred at 100° C. under nitrogenovernight. The reaction was removed from the heat, quenched with ice,and brought to pH 12 with 1N NaOH. Extraction with EtOAc (2×) andwashing the combined organic layers with brine and drying over MgSO₄afforded 0.14 g of crude product after evaporation of the solvent. Flashchromatography (SiO₂, 0.1 to 10% 2 N ammonia in MeOH/CH₂Cl₂) affordedpure product (34 mg, 17% yield). MS (ESI) 217 (M+H).

Example 210 Preparation of(3S,11aR)-1,2,3,4,11,11a-hexahydro-3-methyl-pyrazino[1,2-b]isoquinolin-6-one

Step A. Preparation of[N-(tert-butyloxycarbonyl)-R-phenylalanyl]-N-(benzyl)-S-alanine, methylester

To a stirring solution of N-(tert-butyloxycarbonyl)-(R)-phenylalanine(1.8 g, 6.8 mmol) and N-benzyl-(L)-alanine, methyl ester (1.7 g, 7.4mmol) in dry DMF(10 mL) at 0° C. was added pyBOP (4.1 g, 8.0 mmol)followed by triethylamine (2.4 ml, 16 mmol). After stirring at ambienttemperature for 3 days, the reaction was transferred to a separatoryfunnel with EtOAc. Extraction with EtOAc and washing of the organiclayer with water, saturated NaHCO₃, and brine and drying with MgSO₄afforded 5.0 g of crude product after evaporation of the solvent.Purification by flash chromatography (SiO₂, 15% EtOAc in CH₂Cl₂)afforded pure product (2.1 g, 66% yield). MS (ESI) 441 (M+H).

Step B. Preparation of (3S,6R)-1,3-Dibenzyl-6-methylpiperazine-2,5-dione

A solution of[N-(tert-butyloxycarbonyl)-R-phenylalanyl]-N-(benzyl)-S-alanine, methylester. (2.0 g, 4.5 mmol) in EtOAc (47 ml) was cooled to 0° C. GaseousHCl was slowly bubbled through the solution for 20 min and then the icebath was removed and the reaction allowed to stir at ambient temperaturefor 20 h. The reaction mixture was evaporated in vacuo and the residuetransferred to a separatory funnel with CH₂Cl₂. Washing the organiclayer with saturated NaHCO₃, and brine and drying with MgSO₄ affordedproduct (0.83 g, 60% yield) after evaporation of the solvent. MS (ESI)309 (M+H). This was used in the next step without further purification.

Step C. Preparation of (2S,5R)-1,5-Dibenzyl-2-methylpiperazine

Lithium aluminum hydride (1 M in THF, 4.8 ml, 4.8 mmol) was addeddropwise over 30 min to a solution of(3S,6R)-1,3-dibenzyl-6-methylpiperazine-2,5-dione (0.39 g, 1.2 mmol) inTHF (7.5 ml) stirring at 0° C. After stirring at 65° C. for 1 day, thereaction was allowed to cool to room temperature and was slowly quenchedwith water (0.34 ml). Sodium hydroxide (1 N, 0.68 ml) and then water(0.51 ml) were added and the gelatinous solid was filtered rinsing withTHF. The filtrate was evaporated in vacuo and the residue transferred toa separatory funnel with EtOAc. Washing the organic layer with brine anddrying with MgSO₄ afforded product (0.40 g) after evaporation of thesolvent. This was used in the next step without further purification.

Step D. Preparation of (2S,5R)-Methyl2,4-dibenzyl-5-methylpiperazine-1-carboxylate

Pyridine (0.57 ml, 7.0 mmol) was added to a stirring solution of(2S,5R)-1,5-dibenzyl-2-methylpiperazine (0.40 g, 1.2 mmol) and methylchloroformate (0.20 ml, 2.5 mmol) in CH₂Cl₂ (14 ml). After stirring atambient temperature for 2 h, the reaction was evaporated in vacuo andthe residue purified by flash chromatography (SiO₂, 3% MeOH in CH₂Cl₂)to afford pure product (0.28 g, 68% yield over the two steps). MS (ESI)339 (M+H).

Step E. Preparation of(3S,11aR)-1,2,3,4,11,11a-Hexahydro-2-benzyl-3-methyl-pyrazino[1,2-b]isoquinolin-6-one

A mixture of (2S,5R)-methyl2,4-dibenzyl-5-methylpiperazine-1-carboxylate (0.28 g, 0.83 mmol),phosphorous oxychloride (5.0 ml) and phosphorous pentoxide (0.48 g, 1.6mmol) was stirred at 100° C. under nitrogen overnight. The reaction wasremoved from the heat, quenched with ice, and brought to pH 7 to 8 with1 N NaOH. Extraction with EtOAc (3×) and washing the combined organiclayers with brine and drying over MgSO₄ afforded 0.11 g of crude productafter evaporation of the solvent. Flash chromatography (SiO₂, CH₂Cl₂ to60% EtOAc in CH₂Cl₂) afforded pure product (47 mg, 19% yield). MS (ESI)307 (M+H).

Step F. Preparation of(3S,11aR)-1,2,3,4,11,11a-hexahydro-3-methyl-pyrazino[1,2-b]isoquinolin-6-one

(3S,11aR)-1,2,3,4,11,11a-Hexahydro-2-benzyl-3-methyl-pyrazino[1,2-b]isoquinolin-6-one(77 mg, 0.25 mmol) and 10% palladium on carbon (25 mg) in methanol (6.5ml) was stirred under a balloon of hydrogen for 3 days. Evapoaration ofthe filtrate after filtration through Celite® afforded 39 mg of crudeproduct. Flash chromatography (SiO₂, 10% 1 N ammonia in MeOH/CH₂Cl₂)gave pure(3,11aR)-1,2,3,4,11,11a-hexahydro-3-methyl-pyarzino[1,2-b]isoquinolin-6-one(29 mg, 54% yield). MS (ESI) 217 (M+H).

Example 211 Preparation of(4R,11aR)-1,2,3,4,11,11a-Hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-oneand(4S,11aS)-1,2,3,4,11,11a-Hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one

Step A. Preparation of (R)-Methyl1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

D-Phenylalanine methyl ester (1.56 g of HCl salt, Aldrich in CH₂Cl₂washed with saturated NaHCO₃ and dried, 7.3 mmol) anddiisopropylethylamine (2.1 ml, 8.9 mmol) in 1,2-dichloroethane (13 ml)was added dropwise over 30 min to a stirring solution of triphosgene(1.1 g, 5.2 mmol) in 1,2-dichloroethane (13 ml). After stirring atambient temperature for 1.5 h, the reaction was cooled to 0° C. andaluminum chloride (2.2 g) was added. After refluxing for 2.5 h, thereaction was once again cooled to 0° C. and quenched by slowly addingwater (13 ml). After stirring for 1 h, the reaction mixture wastransferred to a separatory funnel with CH₂Cl₂. Extraction with CH₂Cl₂(2×) and drying over MgSO₄ afforded 1.8 g of crude product. Flashchromatography (SiO₂, 0 to 100% EtOAc in CH₂Cl₂) afforded pure product(0.65 g, 43% yield). MS (ESI) 206 (M+H).

Step B. Preparation of Methyl2-(1-methoxy-1-oxopropan-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

Sodium hydride (60% oil dispersion, 0.51 g, 12.4 mmol) was added to astirring solution of (R)-methyl1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1.3 g, 6.2 mmol) inDMF (13 ml). After stirring for 30 min at ambient temperature, methyl2-bromopropionate (1.1 ml, 9.3 mmol) was added. After stirring at 40° C.for 2 h, the reaction was removed from the heat and quenched with water.The reaction mixture was transferred to a separatory funnel withEtOAc/water. Extraction with EtOAc (2×) and washing the combined organiclayers with saturated NaHCO₃, water, and brine and drying over MgSO₄afforded 2.0 g of crude product after evaporation of the solvent. Flashchromatography (SiO₂, hexanes to 80% EtOAc in hexanes) afforded Isomer A(0.53 g, 29% yield), Isomer B (0.28 g, 15% yield) and a mixture of thetwo isomers (0.28 g, 15% yield). All have MS (ESI) 292 (M+H).

Step C. Preparation of3-(Hydroxymethyl)-2-(1-hydroxypropan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

Isomer B of methyl2-(1-methoxy-1-oxopropan-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate(0.28 g, 0.96 mmol) in THF (9.8 ml) was added to a stirring solution ofLiBH₄ (2.0 M in THF, 0.58 ml, 1.2 mmol) in THF (1.5 ml). After refluxingfor 1.5 h, the reaction was cooled to room temperature and quenched with0.036 ml of water. Sodium hydroxide (1N, 0.072 ml) and then water (0.054ml) were added. The reaction mixture was filtered through Celite,rinsing with THF. Evaporation of the filtrate afforded 0.32 g of crudeproduct. Flash chromatography (SiO₂, 0.5 to 10% MeOH in CH₂Cl₂) affordedpure product (0.20 g, 89% yield). MS (ESI) 236 (M+H).

Step D. Preparation of3-(Chloromethyl)-2-(1-chloropropan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

3-(Hydroxymethyl)-2-(1-hydroxypropan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one(from Isomer B, 0.20 g, 0.85 mmol) in chloroform (7.6 ml) was added to astirring solution of thionyl chloride (1.8 ml) in chloroform (10 ml).After refluxing overnight the condenser was removed and the majority ofthe solvent allowed to evaporate over the next 4 h. The residue waspurified by flash chromatography (SiO₂, CH₂Cl₂ to 50% EtOAc in CH₂Cl₂)affording pure product (0.16 g, 69% yield). MS (ESI) 273/275 (M+H).

Step E. Preparation of1,2,3,4,11,11a-Hexahydro-2-benzyl-4-methyl-pyrazino[1,2-b]isoquinolin-6-one

A mixture of3-(chloromethyl)-2-(1-chloropropan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one(from Isomer B, 0.16 g, 0.58 mmol), K₂CO₃ (0.16 g, 1.2 mmol), andbenzylamine (0.075 ml, 0.67 mmol) in diglyme (1.5 ml) was heated atreflux for 6 h. After cooling to room temperature the reaction wastransferred to a separatory funnel with ether and water. Extraction withether and washing the organic layer with water (4×) and brine, anddrying over MgSO₄ afforded 0.15 g of crude product after evaporation ofthe solvent. Flash chromatography (SiO₂, hexanes to 60% EtOAc inhexanes) afforded pure product (93 mg, 52% yield). MS (ESI) 307 (M+H).

Step F. Preparation of(4R,11aR)-1,2,3,4,11,11a-Hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-oneand(4S,11aS)-1,2,3,4,11,11a-Hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one

1,2,3,4,11,11a-Hexahydro-2-benzyl-4-methyl-pyrazino[1,2-b]isoquinolin-6-one(from Isomer B, 93 mg, 0.30 mmol) and 10% palladium on carbon (40 mg) inEtOAc (9 ml) was stirred under a balloon of hydrogen. After 3 days thereaction was about 60% complete by HPLC. The catalyst was filtered offand then fresh catalyst added. After stirring an additional day under aballoon of hydrogen, the reaction was filtered through Celite® rinsingwith EtOAc and methanol to afford 56 mg of crude product. Columnpurification (Chiralcel OD, 15% 1/1 MeOH/EtOH in hexanes) afforded pure(4R,11aR)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one(18 mg, 28% yield). MS (ESI) 217 (M+H). Further elution afforded pure(4S,11aS)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one(16 mg, 25% yield). MS (ESI) 217 (M+H).

Example 212 Preparation of(4R,11aR)-1,2,3,4,11,11a-Hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one,and(4S,11aS)-1,2,3,4,11,11a-Hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one

The title compounds were prepared according to procedures described inExample 211 except that the Isomer B and Isomer A were not separateduntil after Step E. Isomer B was then submitted to the reactionconditions below.

Step F. Preparation of(4R,11aR)-1,2,3,4,11,11a-Hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one,and(4S,11aS)-1,2,3,4,11,11a-Hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one

1,2,3,4,11,11a-Hexahydro-2-benzyl-4-methyl-pyrazino[1,2-b]isoquinolin-6-one(from Isomer B, 12 mg, 0.04 mmol) and 10% palladium on carbon (5 mg) inMeOH (1 ml) was stirred under a balloon of hydrogen. The catalyst wasfiltered off and then fresh catalyst added. After stirring an additional4 h at 40° C. under a balloon of hydrogen, the reaction was filteredthrough Celite® rinsing with methanol to afford 8 mg of crude product.Column purification (Chiralcel OD, 10% 1/1 MeOH/EtOH in hexanes)afforded pure(4R,11aR)-1,2,3,4,11,11a-hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one(1.5 mg, 17% yield) MS (ESI) 231 (M+H). Further elution afforded (4S,1aS)-1,2,3,4,11,11a-hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one(1.6 mg, 18% yield) MS (ESI) 231 (M+H). Further elution also provided(4R,11aR)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one(2.4 mg, 29% yield) and(4S,11aS)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one(2.2 mg, 27% yield).

Example 213 Preparation of(4S,11aR)-1,2,3,4,11,11a-Hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-oneand(4R,11aS)-1,2,3,4,11,11a-Hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one

The title compounds were prepared according to procedures described inExample 211 except that the Isomer A was utilized throughout thesequence to afford(4S,11aR)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one.[MS (ESI) 217 (M+H)] and (4R,11aS)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one[MS (ESI) 217 (M+H)].

Example 214 Preparation of(11aR)-1,3,4,6,11,11a-Hexahydro-4-methyl-2H-pyrazino[1,2-b]isoquinoline

Step A. Preparation of (3R)-tert-Butyl3-(methoxy(methyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a stirring solution of(R)-N-(tert-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (Fluka, 1.4 g, 5.0 mmol) in dry CH₂Cl₂ (31 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.3 g, 8.4mmol) and 1-hydroxybenzotriazole hydrate (0.76 g, 5.8 mmol). Thereaction was stirred at ambient temperature for 20 min and thenN,O-dimethylhydroxyamine hydrochloride (0.75 g, 7.5 mmol) andtriethylamine (1.2 ml, 7.7 mmol) were added. After stirring at ambienttemperature for 1.5 hour, the reaction was transferred to a separatoryfunnel with CH₂Cl₂. Extraction with CH₂Cl₂ and washing of the organiclayer with water, saturated NaHCO₃, and brine and drying with MgSO₄afforded product (1.7 g, 100% yield). MS (ESI) 221 (M+H−BOC). This wasused in the next step without further purification.

Step B. (3R)-tert-Butyl3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

Lithium aluminum hydride (1 M in THF, 5.3 ml, 5.3 mmol) was added to asolution of (3R)-tert-butyl3-(methoxy(methyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.7 g, 5.0 mmol theory) in ether (16 ml) stirring at 0° C. undernitrogen. After stirring at 0° C. for 1 h, the reaction was slowlyquenched with water (0.40 ml). Sodium hydroxide (1N, 0.80 ml) followedby water (0.60 ml) were then added and the resultant gelatinousprecipitate was filtered through Celite® rinsing with ether and THF. Thefiltrate was evaporated and the residue transferred to a separatoryfunnel with EtOAc. Washing with brine and drying with MgSO₄ affordedcrude product (1.3 g, 100% yield) which was used in the next stepwithout further purification.

Step C. Preparation of (3R)-tert-Butyl3-((2,4-dimethoxybenzylamino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Sodium triacetoxyborohydride (3.1 g, 15 mm) was added to a mixture of(3R)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.3g, 5.0 mmol theory), 2,4-dimethoxybenzylamine (0.77 ml, 5.5 mmol), anddry 4 A sieves in 1,2-dichloroethane (25 ml) stirring at ambienttemperature. After stirring at ambient temperature overnight thereaction solution was transferred to a separatory funnel with EtOAc andsaturated NaHCO₃. Extraction with EtOAc (2×), washing the combinedorganic layers with brine and drying over MgSO₄ afforded 1.6 g of crudeproduct. Flash chromatography (SiO₂, 1 to 10% 2N NH₃ in MeOH/CH₂Cl₂)gave pure product (1.3 g, 63% yield over the previous 3 steps). MS (ESI)413 (M+H).

Step D. Preparation of (3R)-(tert-Butyl3-(N-(2,4-dimethoxybenzyl)-2-chloropropanamido)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

2-Chloropropanoyl chloride (0.19 g, 0.15 ml, 1.5 mmol) was added to asolution of (3R)-tert-butyl3-((2,4-dimethoxybenzylamino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.41 g, 1.0 mmol) in EtOAc (12 ml) stirring at 0° C. followed bysaturated NaHCO₃ (0.65 ml). After stirring at 0° C. for 3 h, thereaction was transferred to a separatory funnel with EtOAc and saturatedNaHCO₃. Extraction with EtOAc (2×), washing the combined organic layerswith brine and drying over MgSO₄ afforded 0.47 g of crude product. Flashchromatography (SiO₂, 0.2 to 10% MeOH in CH₂Cl₂) gave pure product (0.37g, 73%). MS (ESI) 503/505 (M+H).

Step E. Preparation ofN-(2,4-Dimethoxybenzyl)-2-chloro-N-(((3R)-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)propanamide

(3R)-(tert-Butyl3-(N-(2,4-dimethoxybenzyl)-2-chloropropanamido)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.36 g, 0.72 mmol) was stirred at ambient temperature intrifluoroacetic acid (3.5 ml) and CH₂Cl₂ (7 ml). After stirring for 1 h,the solvent was evaporated in vacuo and the residue transferred to aseparatory funnel with CH₂Cl₂. Extraction with CH₂Cl₂ (2×), washing thecombined organic layers with saturated NaHCO₃ and drying over MgSO₄afforded 0.18 g of crude product. This material was used in the nextstep without further purification.

Step F. Preparation of(11aR)-1,2,11,11a-Tetrahydro-2-(2,4-dimethoxybenzyl)-4-methyl-4H-pyrazino[1,2-b]isoquinolin-3(6H)-one

Cesium carbonate (0.18 g) was added to a solution ofN-(2,4-dimethoxybenzyl)-2-chloro-N-(((3R)-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)propanamide(0.18 g, 0.44 mmol) in DMF (4.7 ml). After stirring at ambienttemperature for 3 h, the reaction was transferred to a separatory funnelwith EtOAc. Extraction with EtOAc, washing the organic layer with water(3×) and brine and drying over MgSO₄ afforded 0.15 g of crude product.Flash chromatography (SiO₂, 0.2 to 10% MeOH in CH₂Cl₂) gave pure product(0.11 g, 68%). MS (ESI) 367 (M+H).

Step G. Preparation of(11aR)-1,3,4,6,11,11a-Hexahydro-2-(2,4-dimethoxybenzyl)-4-methyl-2H-pyrazino[1,2-b]isoquinoline

Lithium aluminum hydride (1 M in THF, 0.63 ml, 0.63 mmol) was added to asolution of(11aR)-1,2,11,11a-tetrahydro-2-(2,4-dimethoxybenzyl)-4-methyl-4H-pyrazino[1,2-b]isoquinolin-3(6H)-one(0.11 g, 0.31 mmol) in THF (1.8 ml) stirring in a room temperature bathunder nitrogen. After stirring at 65° C. for 2 h, the reaction wascooled to room temperature and slowly quenched with water (0.18 ml).Sodium hydroxide (1N, 0.36 ml) followed by water (0.27 ml) were thenadded and the resultant gelatinous precipitate was filtered throughCelite® rinsing THF. The filtrate after evaporation of the solvent wastransferred to a separatory funnel with EtOAc. Washing with brine anddrying with MgSO₄ afforded crude product (0.10 g, 95% yield) afterevaporation of the solvent. This material was used in the next stepwithout further purification.

Step H. Preparation of(11aR)-1,3,4,6,11,11a-Hexahydro-4-methyl-2H-pyrazino[1,2-b]isoquinoline

1-Chloroethylchloroformate (0.050 ml, 0.47 mmol) was added to a solutionof (11aR)-2,3,4,6,11,11a-hexahydro-2-(2,4-dimethoxybenzyl)-4-methyl-1H-pyrazino[1,2-b]isoquinoline(53 mg, 0.15 mmol) in 1,2-dichloroethane (1 ml) stirring at 0° C. Theice bath was removed and the reaction stirred at ambient temperature for30 min. After refluxing an additional 2 h, the reaction was evaporatedin vacuo. Methanol (1.0 ml) was added to the residue and the reactionrefluxed under nitrogen for 1 h. Evaporation in vacuo afforded 75 mg ofcrude product. This crude product was transferred to a separatory funnelwith CH₂Cl₂ and saturated NaHCO₃. Extraction with CH₂Cl₂ (2×) and dryingof the combined organic layers over MgSO₄ afforded 42 mg which wasfurther purified by flash chromatography (SiO₂, 0.2 to 10% 2N NH₃ inMeOH/CH₂Cl₂) to give pure product (17 mg, 55%). MS (ESI) 203 (M+H).

Example 215(−)-1,2,3,4,11,11a-Hexahydropyrazino[1,2-b][1,2]benzothiazine6,6-dioxide

Step A. Preparation of 2-Bromo-N-(1,1-dimethylpropyl)Benzenesulfonamide

To a solution of 2-methyl-2-butanamine (11.4 mL, 97.8 mmol) indichloromethane (100 mL) was added, dropwise over a 10 min period, asolution of 2-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) indichloromethane (ca. 50 mL). After stirring for 15 h the reaction wasconcentrated in vacuo. The residue was crystallized from methyl t-butylether to provide 10.5 g (87%) of2-bromo-N-(1,1-dimethylpropyl)benzenesulfonamide in two crops: LCMS(neg. ion spectrum) m/z 304/306.

Step B. Preparation of N-(1,1-Dimethylpropyl)2-(2-propenyl)benzenesulfonamide

To a solution of 2-bromo-N-(1,1-dimethylpropyl)benzenesulfonamide (5.00g, 16.3 mmol) in dimethylformamide (dry, N₂-degassed, 20 mL) were addedallyltribuylstannane (6.07 mL, 19.6 mmol) andtetrakis(triphenylphosphine)palladium(0) (189 mg, 0.163 mmol). Themixture was heated at 110° C. for 15 h. The reaction was concentrated invacuo and the residue was chromatographed (silica, 40%dichloromethane/hexanes to dichloromethane gradient) to provideN-(1,1-dimethylpropyl) 2-(2-propenyl)benzenesulfonamide (4.04 g, 92%) asan off-white solid: LCMS (neg. ion spectrum) m/z 266.

Step C. Preparation of 2-(2-Propenyl)benzenesulfonamide

Ice-cold trifluoroacetic acid (50 mL) was added to ice-coldN-(1,1-dimethylpropyl) 2-(2-propenyl)benzenesulfonamide (4.04 g, 15.1mmol). The reaction was stirred at 0° C. for 3.5 h. The reaction wasconcentrated in vacuo and the residue was crystallized from methyltert-butyl ether/hexanes to provide 2-(2-propenyl)benzenesulfonamide aswhite plates (2.53 g, 85%) in one crop: LCMS (neg. ion spectrum) m/z196.

Step D. Preparation of 8,8a-Dihydro-1H-azirino[1,2-b][1,2]benzothiazine3,3-dioxide

Iodine (6.51 g, 26.7 mmol) was added in one portion to a solution of2-(2-propenyl)benzenesulfonamide (2.53 g, 12.8 mmol) in N₂-degasseddichloromethane (125 mL) containing potassium carbonate (7.09 g, 51.3mmol). After stirring for 20 min, water (50 mL, containing 2 g of sodiummetabisulfite) was carefully added. The layers were separated and theaqueous layer was extracted with dichloromethane (25 mL). The combinedorganic layers were washed with water (25 mL). To the combined organiclayers were added methanol (50 mL) and 0.25 N potassium carbonate in 70%aqueous methanol. After stirring for 10 min, sodium metabisulfite (100mg) was added to discharge the color. The volatile organic solvents wereremoved in vacuo. The residue was partitioned between dichloromethane(100 mL) and additional water (30 mL). The aqueous layer was extractedwith dichloromethane (25 mL). The combined organic layers were dried(magnesium sulfate) and concentrated in vacuo to provide8,8a-dihydro-1H-azirino[1,2-b][1,2]benzothiazine 3,3-dioxide as a paleyellow oil which solidified (2.25 g, 90%): LCMS (pos. ion spectrum) m/z237 (M+H+CH₃CN).

Step E. Preparation of1,1-Dimethylethyl[(3,4-dihydro-1,1-dioxido-2H-1,2-benzothiazin-3-yl)methyl]-2-propenylcarbamate

A solution of 8,8a-dihydro-1H-azirino[1,2-b][1,2]benzothiazine3,3-dioxide (514 mg, 2.63 mmol), triethylamine (0.37 mL, 2.6 mmol), and2-propenamine (0.99 mL, 13 mmol) in tetrahydrofuran (25 mL) was heatedat 100° C. in a sealed pressure tube for 14 h. The cooled reaction wasconcentrated in vacuo to provide a yellow solid. The solid was taken upin tetrahydrofuran (5 mL). Water (3 mL), 1 N NaOH (2.9 mL) andbis(1,1-dimethylethyl) dicarbonate (861 mg, 3.94 mmol) were sequentiallyadded. After stirring for 10 min, the reaction was diluted with water(25 mL) and the mixture was extracted with dichloromethane (2×25 mL).The combined organic layers were dried (magnesium sulfate) andconcentrated in vacuo. The residue was chromatographed (silica, 10%ethyl acetate/hexanes to ethyl acetate gradient) to provide1,1-dimethylethyl[(3,4-dihydro-1,1-dioxido-2H-1,2-benzothiazin-3-yl)methyl]-2-propenylcarbamate(587 mg, 63%) as a colorless oil: LCMS (neg. ion spectrum) m/z 351.

Step F. Preparation of1,1-Dimethylethyl[(3,4-dihydro-1,1-dioxido-2H-1,2-benzothiazin-3-yl)methyl]-(2-hydroxyethyl)carbamate

To a stirred solution of1,1-dimethylethyl[(3,4-dihydro-1,1-dioxido-2H-1,2-benzothiazin-3-yl)methyl]-2-propenylcarbamate(499 mg, 1.42 mmol) in dioxane (25 mL) was added, sequentially, sodiummetaperiodate (1.21 g, 5.66 mmol) and osmium tetraoxide (2% w/v inwater, 1.8 mL, 0.14 mmol). After stirring for 1.5 h, the thick slurrywas diluted with water (75 mL). The mixture was extracted withdichloromethane (3×50 mL). The combined organic layers were washed withsaturated sodium chloride (50 mL), 5% sodium thiosulfate (3×50 mL),dried (sodium sulfate), and concentrated in vacuo to an oil. To a 0° C.solution of this residue in ethanol (5 mL) was added sodium borohydride(54 mg, 1.42 mmol). After 10 min, acetone (1 mL) was added. The reactionwas concentrated in vacuo. The residue was partitioned between water (15mL) and dichloromethane (15 mL). The aqueous phase was extracted withdichloromethane (15 mL). The combined organic layers were dried(magenesium sulfate) and concentrated in vacuo. The residue waschromatographed (silica, 50% ethyl acetate/hexanes to ethyl acetategradient) to provide1,1-dimethylethyl[(3,4-dihydro-1,1-dioxido-2H-1,2-benzothiazin-3-yl)methyl]-(2-hydroxyethyl)carbamateas a colorless foam (276 mg, 55%): LCMS (neg. ion spectrum) m/z 355.

Step G. Preparation of 1,1-dimethylethyl3,4,11,11a-tetrahydropyrazino[1,2-b][12]benzothiazine-2(1H)-carboxylate6,6-dioxide

To a 0° C. solution of1,1-dimethylethyl[(3,4-dihydro-1,1-dioxido-2H-1,2-benzothiazin-3-yl)methyl]-(2-hydroxyethyl)carbamate(276 mg, 0.774 mmol) in dichloromethane (5 mL, dried by passage throughAct I neutral alumina) were added triethylamine (0.160 mL, 1.16 mmol)and methanesulfonyl chloride (0.072 mL, 0.929 mmol) sequentially. After30 min, an additional 0.14-mL portion of methanesulfonyl chloride wasadded. After an additional 20 min, the reaction was diluted withdichloromethane (25 mL) and was washed with half-saturated sodiumbicarbonate (10 mL). The organic layer was dried (sodium sulfate) andconcentrated in vacuo to provide a colorless foam (349 mg). To asolution of this residue in tetrahydrofuran (25 mL) was added potassiumtert-butoxide (99 mg, 0.883 mmol). After 1 h, an additional 10-mgportion of potassium tert-butoxide was added. After 10 min, the reactionwas partitioned beteween dichloromethane (75 mL) and saturated sodiumchloride (25 mL). The organic layer was dried (magnesium sulfate) andconcentrated in vacuo. The residue was chromatographed (silica,dichloromethane then 10% methanol/dichloromethane) and repurified bychromatography (silica, 10% ethyl acetate to ethyl acetate gradient) toprovide 1,1-dimethylethyl1,2,3,4,11,11a-hexahydropyrazino[1,2-b][1,2]benzothiazine-2-carboxylate6,6-dioxide as an oil (151 mg, 56%): LCMS (pos. ion spectrum) m/z 694(2M+H).

Step H. Preparation of(−)-1,2,3,4,11,11a-hexahydropyrazino[1,2-b][1,2]benzothiazine6,6-dioxide

Cold trifluoroacetic acid (2 mL) was added to cold 1,1-dimethylethyl1,2,3,4,11,11a-hexahydropyrazino[1,2-b][1,2]benzothiazine-2-carboxylate6,6-dioxide (151 mg, 0.446 mmol). After 1 h, the reaction wasconcentrated in vacuo. The residue was partitioned betweendichloromethane (10 mL) and 0.5 N sodium carbonate (2 mL). The organiclayer was dried (sodium sulfate) and concentrated in vacuo. The residuewas chromatographed (Diacel Chiracel OJ, 5×50 cm, 35% 1:1methanol/ethanol:hexanes containing 0.3% triethylamine, 50 mL/min).Fractions containing the more rapidly eluting enantiomer concentrated invacuo. The residue was taken up in 50% aqueous methanol (1 mL) and wasloaded onto a 1-g methanol-activated water-equilibrated SCX-type cationexchange column. The column was washed with water (5 mL) and 25% aqueousmethanol (5 mL). The column was eluted with 2 N methanolic ammonia.Concentration of this fraction in vacuo provided(−)1,2,3,4,11,11a-hexahydropyrazino[1,2-b][1,2]benzothiazine6,6-dioxide: LCMS (pos. ion spectrum) m/z 239.

Example 216 Preparation of(+)-1,2,3,4,11,11a-Hexahydropyrazino[1,2-b][1,2]benzothiazine6,6-dioxide

Product-containing fractions from the chiral chromatographic separationin Example 215 Step H were concentrated in vacuo to provide the titlecompound: LCMS (pos. ion spectrum) m/z 239.

Example 217 Preparation of(−)-1,2,3,4,11,11a-Hexahydro-2-methyl-pyrazino[1,2-b][1,2]benzothiazine6,6-dioxide

Step A. Preparation of(−)-1,2,3,4,11,11a-Hexahydro-2-methyl-pyrazino[1,2-b][1,2]benzothiazine6,6-dioxide

To a solution of the title compound of Example 215 (23.0 mg, 0.0965mmol) in dimethylformamide (0.75 mL) were added cesium carbonate (94 mg,0.29 mmol) and methyl iodide (0.0072 mL, 0.12 mmol). After 4.5 h, thereaction was partitioned between dichloromethane (2 mL) and water (2mL). The aqueous layer was extracted with dichloromethane (2 mL). Thecombined organic layers were dried (sodium sulfate) and concentrated invacuo. The residue was taken up in a minimum amount of 50% aqueousmethanol and loaded onto a methanol-activated water-equilibrated 1-gSCX-type cation exchange column. The column was washed with water (6 mL)and 50% aqueous methanol (6 mL). The column was eluted with 2Nmethanolic ammonia (8 mL). This fraction was concentrated in vacuo toprovide(−)-1,2,3,4,11,11a-hexahydro-2-methyl-pyrazino[1,2-b][1,2]benzothiazine6,6-dioxide as a white solid (19 mg, 79%): LCMS (pos. ion spectrum) m/z253.

Example 218 Preparation of(+)-1,2,3,4,11,11a-Hexahydro-2-methyl-pyrazino[1,2-b][1,2]benzothiazine6,6-dioxide

Step A. Preparation of the(+)-1,2,3,4,11,11a-hexahydro-2-methyl-pyrazino[1,2-b][1,2]benzothiazine6,6-dioxide

As described for Example 217, the title compound (20 mg, 65%) wasprepared from the title compound of Example 216 (29 mg, 0.122 mmol):LCMS (pos. ion spectrum) m/z 253.

Example 219 Preparation of1,2,3,4,11,11a-Hexahydro-8-(trifluoromethyl)pyrazino[1,2-b][1,2]benzothiazine6,6-dioxide

Step A. Preparation of8,8a-Dihydro-5-(trifluoromethyl)-1H-azirino[1,2-b][1,2]benzothiazine3,3-dioxide

As described in steps Example 215 Steps A–C,2-(2-propenyl)-5-trifluoromethylbenzenesulfonamide was prepared from5-trifluoromethyl-2-bromobenzenesulfonyl chloride. The intermediate2-bromo-N-(1,1-dimethyl-2-propyl)-5-trifluoromethylbenzenesulfonamidewas recrystallized from toluene; andN-(1,1-dimethyl-2-propyl)-2-(2-propenyl)-5-trifluoromethylbenzenesulfonamideand intermediates 2-(2-propenyl)-5-trifluoromethylbenzenesulfonamidewere chromatographed using ethyl acetate-hexanes gradients.

To a solution of 2-(2-propenyl)-5-trifluoromethylbenzenesulfonamide (780mg, 2.94 mmol) in nitrogen-degassed dichloromethane (30 mL) containingpotassium carbonate (1.62 g, 11.8 mmol) was added iodine (1.49 g, 5.88mmol). After stirring for 2 h, the reaction was quenched with 10%aqueous sodium thiosulfate (ca. 14 mL). The dichloromethane was removedin vacuo and the residue was diluted with methanol (10 mL) and 0.25 Npotassium carbonate in 70% aqueous methanol. Additional methanol wasadded to produce a nearly homogeneous solution. After 10 min, thereaction was concentrated in vacuo to remove most of the methanol. Theresidue was partitioned between dichloromethane (30 mL) and water (10mL). The aqueous layer was extracted with dichloromethane (5 mL) and thecombined organic layers were dried (magnesium sulfate) and concentratedin vacuo to provide8,8a-dihydro-5-(trifluoromethyl)-1H-azirino[1,2-b][1,2]benzothiazine3,3-dioxide as a white solid (685 mg (92%): LCMS (net. ion spectrum) m/z262.

Step B. Preparation of3,4-dihydro-N-(2-hydroxyethyl)-7-(trifluoromethyl)-2H-1,2-benzothiazine-3-methanamine1,1-dioxide

A solution of8,8a-dihydro-5-(trifluoromethyl)-1H-azirino[1,2-b][1,2]benzothiazine3,3-dioxide (685 mg, 0.260 mmol), ethanolamine (0.785 mL, 13.0 mmol) andtriethylamine (0.33 mL, 2.6 mmol) in tetrahydrofuran (25 mL) was heatedin a sealed tube at 100° C. for 3 h. The cooled reaction wasconcentrated in vacuo. The residue was chromatographed (silica, 2%–20%methanol/dichloromethane gradient) to provide3,4-dihydro-N-(2-hydroxyethyl)-7-(trifluoromethyl)-2H-1,2-benzothiazine-3-methanamine1,1-dioxide as a white solid (124 mg) and additional impure material:LCMS (neg. ion spectrum) m/z 323.

Step C. Preparation ofPhenylmethyl[(3,4-dihydro-1,1-dioxido-7-(trifluoromethyl)-2H-1,2-benzothiazin-3-yl)methyl](2-hydroxyethyl)carbamate

To a solution of3,4-dihydro-N-(2-hydroxyethyl)-7-(trifluoromethyl)-2H-1,2-benzothiazine-3-methanamine1,1-dioxide (124 mg, 0.382 mmol) in tetrahydrofuran (4 mL) was added,sequentially, 0.5 N aqueous sodium carbonate (2 mL, 1 mmol) and benzylchloroformate (0.066 mL, 0.46 mmol). The reaction was stirred for 25min. The layers were separated and the aqueous layer was extracted withdichloromethane (5 mL). The combined organic layers were washed withsaturated sodium chloride (5 mL) and were concentrated in vacuo. To theresidue taken up in methanol (5 mL) was added 2 N potassium hydroxide(0.5 mL). After 15 min, the reaction was brought to pH 4 with 1 N HCl.The reaction was concentrated in vacuo to remove the methanol. Theresidue was partitioned between dichloromethane (10 mL) and water (5mL). The organic layer was dried (magnesium sulfate) and concentrated invacuo to provide a yellow oil. Chromatography of this residue (silica,30% ethyl acetate/hexanes to ethyl acetate gradient) provided 90 mg(51%) of aphenylmethyl[(3,4-dihydro-1,1-dioxido-7-(trifluoromethyl)-2H-1,2-benzothiazin-3-yl)methyl](2-hydroxyethyl)carbamateas a white solid: LCMS (neg. ion spectrum) m/z 457.

Step D. Preparation of phenylmethyl3,4,11,11a-Tetrahydro-8-(trifluoromethyl)pyrazino[1,2-b][1,2]benzothiazine-2(1H)-carboxylate6,6-dioxide

To a 0° C. solution ofphenylmethyl[(3,4-dihydro-1,1-dioxido-7-(trifluoromethyl)-2H-1,2-benzothiazin-3-yl)methyl](2-hydroxyethyl)carbamate(400 mg, 0.873 mmol) in dichloromethane (20 mL, dried by passage throughAct I neutral alumina) was added triethylamine (0.243 mL, 1.74 mmol) andmethanesulfonic anhydride (228 mg, 1.31 mmol). After 3 h, an additional70-mg portion of methanesulfonic anhydride was added. After anadditional 1 h, a 228-mg portion of methanesulfonic anhydride and a0.243-mL portion of triethylamine were added. After 10 min, the reactionwas diluted with dichloromethane (20 mL), washed with saturated sodiumbicarbonate (10 mL), dried (sodium sulfate) and concentrated in vacuo.To a 0° C. solution of this residue in tetrahydrofuran (10 mL) wasadded, dropwise, lithium bis(trimethylsilyl)amide (1 N intetrahydrofuran, 1.10 mL, 1.10 mmol). After 20 min, an additional0.15-mL portion of lithium bis(trimethylsilyl)amide was added dropwiseto produce an orange solution. The reaction was diluted with saturatedsodium chloride (20 mL). The aqueous layer was extracted withdichloromethane (2×20 mL). The combined organic layers were dried(sodium sulfate) and concentrated in vacuo. The residue was purified bychromatography (silica, 10% ethyl acetate/hexanes to ethyl acetategradient) to provide phenylmethyl3,4,11,11a-tetrahydro-8-(trifluoromethyl)pyrazino[1,2-b][1,2]benzothiazine-2(1H)-carboxylate6,6-dioxide (321 mg, 83%) as a white foam.: LCMS (neg. ion spectrum) m/z439.

Step E. Preparation of1,2,3,4,11,11a-Hexahydro-8-(trifluoromethyl)-pyrazino[1,2-b][1,2]benzothiazine6,6-dioxide

To a solution of phenylmethyl3,4,11,11a-tetrahydro-8-(trifluoromethyl)pyrazino[1,2-b][1,2]benzothiazine-2(1H)-carboxylate6,6-dioxide (59.0 mg, 0.134 mmol) in methanol (2 mL) under a nitrogenatmosphere was added 10% Pd-C (6 mg). The nitrogen atomosphere wasexchanged for hydrogen (provided by a balloon) using 3 pump/purgecycles. The reaction was stirred for 1 h. The hydrogen atmosphere wasexchanged for nitrogen and the reaction was filtered through Celite®AFA. The pad was rinsed with methanol (1 mL). The combined filtrateswere concentrated in vacuo to provide the title compound: LCMS (pos. ionspectrum) m/z 307.

Example 220 Preparation of(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-[benzyl-[2-tert-butoxycarbonylamino-3-(4-trifluoromethyl-phenyl)-propionyl]-amino]-aceticacid ethyl ester

To a stirred solution ofN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine (1.0 g, 3.0 mmol,Synthetech) and EDC (0.69 g, 3.6 mmol) in dry CH₂Cl₂ (15 mL),N-benzylglycine ethyl ester (0.7 g, 3.6 mmol) followed by DMAP (0.07 g,0.57 mmol) was added. The reaction was stirred for 20 h and then dilutedwith EtOAc (70 mL), washed with 1N HCl (15 mL), saturated NaHCO₃ (15 mL)and brine (15 mL). The organic layer was dried over MgSO₄, and conc invacuo to yield 1.5 grams (98%) of the product as a colorless oil. MS(ESI) 509 (M+H).

Step B. Preparation of(R)-1-benzyl-3-(4-trifluoromethyl-benzyl)-piperazine-2,5-dione

To a stirred solution of[benzyl-[2-tert-butoxycarbonylamino-3-(4-trifluoromethyl-phenyl)-propionyl]-amino]-aceticacid ethyl ester (1.5 g, 2.95 mmol) in dry CH₂Cl₂ (50 mL), 4N HCl indioxane (25 mL, Aldrich) was added and stirred at room temperature for 2h and then conc in vacuo. The rxn product was partitioned between CH₂Cl₂(100 mL) and saturated NaHCO₃ (20 mL). The organic layer was separated,dried over MgSO₄ and conc in vacuo to give a clear oil. The oil wasdiluted in dichloroethane (50 mL) and stirred in 60° C. bath for 2 h toyield 1.02 g (95%) of the product as a off white solid. MS (ESI) 363(M+H).

Step C. Preparation of(R)-1-benzyl-3-(4-trifluoromethyl-benzyl)-piperazine

To a stirred solution of1-benzyl-3-(4-trifluoromethyl-benzyl)-piperazine-2,5-dione (0.53 g, 1.46mmol) in dry THF (15 mL), 1M LAH in THF (6.14 mL, Aldrich) was slowlyadded at 0° C. and then heated to reflux for 18 h under argon. Thereaction was cooled to room temperature and carefully quenched with H₂O(1 mL), 1N NaOH (1 mL) and H₂O (1 mL). The reaction mixture was filteredthrough bed of celite and rinsed with THF (100 mL). The filtrate wasconc in vacuo and then dissolved in EtOAc (100 mL), washed with brine(2×10 mL), dried over MgSO₄, and conc in vacuo to yield 0.45 g (92%) ofthe product as a colorless oil. MS (ESI) 335 (M+H).

Step D. Preparation of(R)-4-benzyl-2-(4-trifluoromethyl-benzyl)-piperazine-1-carboxylic acidmethyl ester

To a stirred solution of 1-benzyl-3-(4-trifluoromethyl-benzylpiperazine(0.44 g, 1.32 mmol) in dry CH₂Cl₂ (10 mL), methylchloroformate (137 mg,1.45 mmol) followed by pyridine (0.5 mL) was added. The reaction wasstirred for 5 h and conc in vacuo and purified by prep TLC (SiO2, 95:5,CH₂Cl₂:MeOH) to yield 0.29 g (56%) of the product as a white solid. MS(ESI) 393 (M+H).

Step E. Preparation of(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Mixture of 4-benzyl-2-(4-trifluoromethyl-benzyl)-piperazine-1-carboxylicacid methyl ester (160 mg, 0.4 mmol) and P₂O₅ (232 mg, 0.8 mmol) inPOCl₃ (2 mL) was stirred at 100° C. for 18 h. The reaction mixture wascooled to room temperature and more P₂O₅ (100 mg, 0.35 mmol) was addedand heated to 100° C. for 24 h and then cooled to RT to give very darkreaction mixture. The reaction was carefully quenched with ice (20 g)and adjusted pH to 9 with saturated Na₂CO₃ solution. The mixture wasextracted with EtOAc (2×70 mL) and combined organic layers were washedwith brine (15 mL), dried over Na₂SO₄, and conc in vacuo to give crudeproduct. Purification on prep HPLC (Phenomenex Luna 5u C18 21.2×100,H2O/MeOH/0.1% TFA) and lyophilization yielded 80 mg (42%) of the productas a off white oil. MS (ESI) 361 (M+H).

Example 221 Preparation of(R)-8-Trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

A mixture of(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(36 mg, 0.076 mmol) and 10% palladium on carbon (10 mg, Aldrich) in MeOH(2 mL) was hydrogenated at 1 atm. The reaction was stirred for 1.5 h.and filtered off the catalyst to give crude product. Purification onprep HPLC (Phenomenex Luna 5u C18 21.2×100, H₂O/MeOH/0.1% TFA) andlyophilization yielded 14.3 mg (49%) of the product as a whitelyophilate. MS (ESI) 271 (M+H).

Example 222 Preparation of(R)-2-Benzyl-10-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 220 with thesubstitution of N-(t-butoxycarbonyl)-D-2-trifluoromethylphenylalaninefor N-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in step A. MS(ESI) 361 (M+H).

Example 223 Preparation of(R)-10-Trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-10-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 271 (M+H).

Examples 224 and 225 Preparation of(R)-2-Benzyl-9-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-2-Benzyl-7-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to the procedures described in Example 220, with thesubstitution of N-(t-butoxycarbonyl)-D-3-trifluoromethylphenylalaninefor N-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in Step A andseparation of regioisomers by prep HPLC (Phenomenex Luna 5u C1821.2×100, H2O/MeOH/0.1% TFA) in Step E. MS (ESI) 361 (M+H) and MS (ESI)361 (M+H).

Examples 226 and 227 Preparation of(R)-9-Trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7-Trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Preparation of(R)-9-Trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-9-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 271 (M+H).

Preparation of(R)-7-Trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-7-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 271 (M+H).

Example 228 Preparation of(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-1-benzyl-3-(4-bromo-benzyl)-piperazine-2,5-dione

Prepared according to the procedures described in Example 220, Step A–B,with the substitution of N-(t-butoxycarbonyl)-D-4-bromophenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in Step A MS (ESI)373 (M+H).

Step B. Preparation of (R)-1-benzyl-3-(4-bromo-benzyl)-piperazine

To (R)-1-benzyl-3-(4-bromo-benzyl)-piperazine-2,5-dione (0.5 g, 1.34mmol) in THF (10 mL) was added 2M BH₃SMe₂ (2.68 mL, 5.36 mmol). Themixture was stirred in RT under argon for 4 days; more 2M BH₃SMe₂ (2.68mL, 5.36 mmol) was added and stirred for 3 days. Reaction mixture wasquenched with EtOH (3 mL) and removed the solvent in rotavap, added EtOH(5 mL) and stirred at 70° C. for 2 hr and concentrated to give colorlessoil as a crude product. MS (ESI) 345 (M+H).

Step C. Preparation of(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to the procedures described in Example 220, Step D–E,with the substitution of (R)-1-benzyl-3-(4-bromo-benzyl)-piperazine for1-benzyl-3-(4-trifluoromethyl-benzylpiperazine in Step D. MS (ESI) 371(M+H).

Example 229 Preparation of(R)-8-Bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

To a stirred solution of(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(25 mg, 0.067 mmol) in dry dichloroethane (1.5 mL),1-chloroethylchloroformate (14.4 mg, 0.1 mmol) was added. The reactionwas stirred for 2 h under reflux and cooled to RT over night. ReactionMixture was concentrated in rotavap. Added MeOH (2 mL) and heated atreflux for 1 hr and conc in vacuo. Took half portion and purified byprep HPLC (Phenomenex Luna 5u C18 21.2×100, H2O/MeOH/0.1% TFA) to yield2.0 mg (15%) of the product as a white lyophilate. MS (ES1) 281 (M+H).

Example 230 Preparation of(R)-8-Cyano-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-8-cyano-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Mixture of(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(25 mg, 0.067 mmol), CuCN (12.9 mg, 0.14 mmol) and CuI (3.7 mg, 0.29mmol) in 1,3-dimethyl-2-imidazolidinone (1.5 mL) was stirred at 190° C.for 83 min in microwave. The reaction was cooled to RT and added EtOAc(20 mL) and H₂O (5 mL). Filtered off the precipitate and rinsed withEtOAc (50 mL). The organic layer was separated and washed with brine (5mL), dried over MgSO₄, and conc in vacuo to give crude product. Purifiedby prep TLC (SiO2, 95:5, CH₂Cl₂:MeOH) to yield crude product as a yellowoil. MS (ESI) 318 (M+H).

Step B. Preparation of(R)-8-Cyano-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to the procedures described in Example 229, with thesubstitution of(R)-2-Benzyl-8-cyano-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 228 (M+H).

Example 231 Preparation of(R)-2-Bezyl-8-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 220 with thesubstitution of N-(t-butoxycarbonyl)-D-4-methoxyphenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in step A. MS(ESI) 323 (M+H).

Example 232 Preparation of(R)-8-Methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Bezyl-8-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 233 (M+H).

Example 233 Preparation of(R)-8-Chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 220 with thesubstitution of N-(t-butoxycarbonyl)-D-4-chlorophenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in step A. Andsubstitution of(R)-2-Benzyl-8-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onein Example 230. MS (ESI) 237 (M+H).

Example 234 Preparation of(R)-8-Fluoro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 220 with thesubstitution of N-(t-butoxycarbonyl)-D-4-chlorophenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in step A. Andsubstitution of(R)-2-Benzyl-8-fluoro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onein Example 222. MS (ESI) 221 (M+H).

Examples 235 and 236 Preparation of(R)-9-Fluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7-Fluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation(R)-2-Benzyl-9-fluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-2-Benzyl-7-fluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to the procedures described in Example 220, with thesubstitution of N-(t-butoxycarbonyl)-D-3-fluoromethylphenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in Step A andpurified by silica gel chromatography, MeOH/CH2Cl2 (0–5% gradient) togive mixture of regioisomers. MS (ESI) 311 (M+H) and MS (ESI) 311 (M+H).

Step B.(R)-9-Fluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-9-fluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 221 (M+H).

Step C.(R)-7-Fluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-7-fluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2b]isoquinolin-6-onfor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 221 (M+H).

Examples 237 and 238 Preparation of(R)-2-Benzyl-9-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-2-Benzyl-7-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to the procedures described in Example 220, with thesubstitution of N-(t-butoxycarbonyl)-D-3-methoxyphenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in Step A andpurified by prep TLC (SiO2, 95:5, CH₂Cl₂:MeOH) to give mixture ofregioisomers. MS (ESI) 323 (M+H) and MS (ESI) 323 (M+H).

Examples 239 and 240 Preparation of(R)-9-Methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7-Methoxy-1,2;3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A.(R)-9-Methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-Benzyl-9-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,111,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 233 (M+H).

Step B.(R)-7-Methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-7-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 233 (M+H).

Example 241 Preparation of(R)-8-Methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-8-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Degassed mixture of(R)-2-Benzyl-8-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(50 mg, 0.13 mmol), trimethylboroxine (25 mg, 0.20 mmol),tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) and K₂CO₃ (56mg, 0.4 mmol) in DMF (1 mL) was heated at 110° C. for 18 h to give darkbrownish reaction mixture. The mixture was then cooled, diluted withethyl acetate(10 mL) and filtered through bed of celite and rinsed withmore ethyl acetate( 20 mL). Filtrate was concentrated and purified byprep TLC (SiO2, 95:5, CH₂Cl₂:MeOH) to give (21 mg, 51%) as a faintyellow oil. MS (ESI) 307 (M+H).

Step D.(R)-8-Methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-8-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 217 (M+H).

Example 242 Preparation of(R)-8-Ethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-8-vinyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Degassed mixture of(R)-2-Benzyl-8-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(50 mg, 0.13 mmol), tributyl(vinyl)tin (64 mg, 0.20 mmol),dichlorobis(triphenylphosphine)palladium (9.1 mg, 0.013 mmol) and LiCl(27.5 mg, 0.65 mmol) in toluene (1 mL) was heated at 110° C. for 18 h togive dark brownish reaction mixture. The mixture was then cooled,diluted with ethyl acetate(10 mL) and filtered through bed of celite andrinsed with more ethyl acetate(20 mL). Filtrate was concentrated andpurified by prep TLC (SiO2, 95:5, CH₂Cl₂:MeOH) to give (25 mg, 60%) as afaint yellow oil. MS (ESI) 319 (M+H).

Step B.(R)-8-Ethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-8-vinyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,111,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 231 (M+H).

Example 243 Preparation of(R)-7-Bromo-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-1-benzyl-3-(5-bromo-2-methoxy-benzyl)-piperazine-2,5-dione

Prepared according to the procedures described in Example 220, Step A–B,with the substitution ofN-(t-butoxycarbonyl)-D-5-bromo-2-methoxyphenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in Step A MS (ESI)405 (M+H).

Step B. Preparation of(R)-1-benzyl-3-(5-bromo-2-methoxy-benzyl)-piperazine

Prepared according to the procedures described in Example 220, Step C,with the substitution of(R)-1-benzyl-3-(5-bromo-2-methoxy-benzyl)-piperazine-2,5-dione for1-benzyl-3-(4-trifluoromethyl-benzyl)-piperazine-2,5-dione and heatingfor only 4 h gave the product MS (ESI) 377 (M+H).

Step C. Preparation of(R)-2-Benzyl-7-bromo-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to the procedures described in Example 220, Step D-E,with the substitution of(R)-1-benzyl-3-(5-bromo-2-methoxy-benzyl)-piperazine for1-benzyl-3-(4-trifluoromethyl-benzylpiperazine in Step D. MS (ESI) 403(M+H).

Step D.(R)-7-Bromo-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 229 with thesubstitution of(R)-2-Benzyl-7-bromo-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 311, 313 (M+H).

Example 244 Preparation of(R)-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-7-bromo-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 233 (M+H).

Example 245 Preparation of(R)-7-Cyano-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-7-cyano-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to the procedures described in Example 230, Step A,with the substitution of(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-7-bromo-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneMS (ESI) 348 (M+H).

Step B. Preparation of(R)-7-Cyano-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 229 with thesubstitution of(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-7-cyano-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 258 (M+H).

Example 246 Preparation of(R)-7-Methyl-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-1-benzyl-3-(5-methyl-2-methoxy-benzyl)-piperazine-2,5-dione

To a degassed mixture of(R)-1-benzyl-3-(5-bromo-2-methoxy-benzyl)-piperazine-2,5-dione (1.91 g,4.74 mmol) and Pd(dppf)Cl₂ (0.12 g, 0.14 mmol) in dioxane (18 mL), 2Mdimethyl zinc in toluene (4.74 mL, 9.48 mmol) was slowly added at 0° C.and heated at reflux for 1 h to give dark brownish reaction mixture. Themixture was then cooled RT and quenched with methanol (10 mL) andfiltered off the precipitate and rinsed with more methanol (20 mL).Filtrate was concentrated and purified (SiO2, 95:5, CH₂Cl₂:MeOH) to give(1.33 g, 83%) as a amber oil. MS (ESI) 339 (M+H).

Step B. Preparation of(R)-7-methyl-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to the procedures described in Example 220, Step C–E,with the substitution of(R)-1-benzyl-3-(5-methyl-2-methoxy-benzyl)-piperazine-2,5-dione for1-benzyl-3-(4-trifluoromethyl-benzyl)-piperazine-2,5-dione in Step C.And substitution of(R)-2-Benzyl-7-methyl-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onein Example 221 to give faint yellow lyophilate MS (ESI) 247 (M+H).

Example 247 Preparation of(R)-7-Methyl-9-ethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-7-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

To a stirred solution of(R)-2-Benzyl-7-methyl-10-methoxy-1,2,3,4,1,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(210 mg, 0.625 mmol) in dry dichloromethane (7 mL), 1M BBr₃ indichloromethane (3.1 mL, 3.1 mmol) was added at −78° C. The reaction wasstirred for 2.5 h at RT under Argon. Slowly quenched with MeOH (5 mL)and conc in vacuo to give light brownish residue. MS (ESI) 323 (M+H).

Step B. Preparation of(R)-2-Benzyl-7-methyl-9-bromo-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

To a stirred solution of(R)-2-Benzyl-7-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(190 mg, 0.59 mmol) in dry CH₂Cl₂:methanol (4:2 mL), tetrabutylammoniumtribromide (331 mg, 0.68 mmol) was added. The reaction was stirred for 1h under Argon added more tetrabutylammonium tribromide (45 mg, 0.09mmol). After 20 min removed solvent in rotavap and then diluted withdichloromethane (100 mL), washed with 5% Na₂S₂O₃ (10 mL), saturatedNaHCO₃ (10 mL) and brine (15 mL). The organic layer was dried overMgSO₄, and conc in vacuo and purified by prep TLC (SiO2, 95:5,CH₂Cl₂:MeOH) to yield 86 mg (36%) of the product as a faint brown oil.MS (ESI) 401, 403 (M+H).

Step C. Preparation of(R)-2-Benzyl-7-methyl-9-ethyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

To a degassed mixture of(R)-2-Benzyl-7-methyl-9-bromo-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(45 mg, 0.11 mmol) and Pd(dppf)Cl₂ (0.12 g, 0.14 mmol) in dioxane (1.25mL), 1.1M diethyl zinc in toluene (0.21 mL, 0.22 mmol) was slowly addedat 0° C. and heated at reflux for 1 h to give dark brownish reactionmixture. The mixture was then cooled RT and quenched with methanol (10mL) and filtered off the precipitate and rinsed with more methanol (20mL). Filtrate was concentrated and purified on prep TLC (SiO2, 95:5,CH₂Cl₂:MeOH) to give (50 mg, 93%) as a faint yellow oil. MS (ESI) 351(M+H).

Step D. Preparation of(R)-2-Benzyl-7-methyl-9-ethyl-10-OTf-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

To a stirred solution of(R)-2-Benzyl-7-methyl-9-ethyl-10-hydroxy-1,2,3,4,11,1a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (50 mg, 0.14 mmol) in dryCH₂Cl₂ (3 mL), trifluoromethanesulfonic anhydride (48 mg, 0.17 mmol)followed by pyridine (82 mg, 1.05 mmol) was added at 0° C. The reactionwas stirred for 2 h in RT under Argon to give burgundy reaction.Quenched with H₂O (10 mL) and extracted with dichloromethane (2×50 mL).Combined organic layers were washed with 1N HCl (10 mL), H₂O (10 mL) anddried over Na₂SO₄, and conc in vacuo to yield 63 mg (94%) of the productas a burgundy oil. MS (ESI) 483 (M+H).

Step E. Preparation of(R)-7-methyl-9-ethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Mixture of(R)-2-Benzyl-7-methyl-9-ethyl-10-OTf-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(30 mg, 0.12 mmol), 10% palladium on carbon (˜30 mg, Aldrich) and Et₃N(25 mg, 0.25 mmol) in MeOH (4 mL) was hydrogenated at 70 psi. Thereaction was stirred for 4 h. and filtered off the catalyst to givecrude product. Purification on prep HPLC (Phenomenex Luna 5 u C1821.2×100, H2O/MeOH/0.1% TFA) and lyophilization yielded 7.4 mg (17%) ofthe product as a faint yellow lyophilate. MS (ESI) 245 (M+H).

Example 248 Preparation of(R)-7,9-di-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-7,9-di-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to procedures described in Example 247, Step C, withthe substitution of 1.0M diethyl zinc in toluene for 1.1M diethyl zincin toluene. MS (ESI) 337 (M+H).

Step B. Preparation of(R)-7,9-di-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-7,9-di-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 247 (M+H).

Examples 249 and 250 Preparation of(R)-8,9-Di-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7,8-Di-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A.(R)-2-Benzyl-8,9-di-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-7,8-di-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to procedures described in Example 220 with thesubstitution of N-(t-butoxycarbonyl)-D-3,4,di-chlorophenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in step A. MS(ESI) 271, 273 (M+H).

Step B. Preparation of(R)-8,9-Di-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7,8-Di-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 229 with thesubstitution of(R)-2-Benzyl-8,9-di-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 271, 273 and 271, 273 (M+H).

Example 251 Preparation of(R)-7-Methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-Benzyl-7-Methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 233 (M+H).

Example 252 Preparation of(R)-9-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-9-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to procedures described in Example 247, Step A, withthe substitution of(R)-2-Benzyl-9-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-7-methyl-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 309 (M+H).

Step B. Preparation of(R)-9-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-9-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 219 (M+H).

Examples 253 and 254 Preparation of(R)-9-Hydroxy-10-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-9-Hydroxy-8,10-dimethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-9-Hydroxy-10-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-9-Hydroxy-8,10-di-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to procedures described in Example 247, Step B, withthe substitution of(R)-2-Benzyl-9-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-7-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand separation of the mono brominated product, MS (ESI) 387, 389 (M+H),and the di-brominated product. MS (ESI) 467 (M+H).

Step B. Preparation of(R)-2-benzyl-9-Hydroxy-10-methy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to procedures described in Example 246, Step A, withthe substitution of(R)-2-Benzyl-9-Hydroxy-10-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor (R)-1-benzyl-3-(5-bromo-2-methoxy-benzyl)-piperazine-2,5-dione. MS(ESI) 323 (M+H).

Step C. Preparation of(R)-2-benzyl-9-Hydroxy-8,10-dimethy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to procedures described in Example 246, Step A, withthe substitution of(R)-2-Benzyl-9-Hydroxy-8,10-di-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor (R)-1-benzyl-3-(5-bromo-2-methoxy-benzyl)-piperazine-2,5-dione. MS(ESI) 337 (M+H).

Step D. Preparation of(R)-9-Hydroxy-10-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-benzyl-9-Hydroxy-10-methy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 233 (M+H).

Step E. Preparation of(R)-9-Hydroxy-8,10-dimethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-benzyl-9-Hydroxy-8,10-dimethy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ES) 247 (M+H).

Examples 255 and 256 Preparation(R)-2-Benzyl-9-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-7-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to the procedures described in Example 220, with thesubstitution of N-(t-butoxycarbonyl)-D-3-chlorophenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in Step A andpurified by silica gel chromatography, MeOH/CH₂Cl₂ (0–5% gradient) togive a mixture of regioisomers (9-Cl: 7-Cl=3:1). A half of the mixturewas separated by chiral prep HPLC (OJ column, 15% iPrOH in Heptane). MS(ESI) 327 (M+H) and MS (ESI) 327 (M+H).

Examples 257 and 258 Preparation of(R)-9-chloro-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7-chloro-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 229 with thesubstitution of a mixture of(R)-2-Benzyl-9-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-7-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 237 (M+H) and 237 (M+H).

Example 259 Preparation of(R)-7-chloro-2,3,4,6,11,11a-hexahydro-1H-pyrazino[1,2-b]isoquinolinedi-trifluoroacetic acid salt

Step A. Preparation(R)-7-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onehydrochloric acid salt

Prepared according to the procedures described in Example 229, with thesubstitution of(R)-2-Benzyl-7-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.The desired crude product was used for next step without furtherpurification MS (ESI) 237 (M+H).

Step B. Preparation of(R)-7-chloro-2,3,4,6,11,11a-hexahydro-1H-pyrazino[1,2-b]isoquinolinedi-trifluoroacetic acid salt

Prepared according to the procedures described in Example 220 step C,with the substitution of(R)-7-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onehydrochloric acid salt for1-benzyl-3-(4-trifluoromethyl-benzyl)-piperazine-2,5-dione. Purificationon prep HPLC (Phenomenex Luna 5 u C18 21.2×100, H2O/MeOH/0.1% TFA) andlyophilization yielded the product as a tan solid. MS (ESI) 223, 225(M+H).

Example 260 Preparation of(R)-9-propyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation(R)-2-Benzyl-9-propyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

A mixture of(R)-9-chloro-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(50 mg, 0.15 mmol), bis(tri-t-butyl phosphine) palladium (2.3 mg, 0.0045mmol), propyl boronic acid (16 mg, 0.18 mmol), and potassium fluoride(19mg, 0.33 mmol) in anhydrous 1,4-dioxane (2 mL) was degassed, heated to100° C. and stirred for 6 h under nitrogen atomsphare. Then the mixturewas cooled down to room temperature, diluted with 10 ml of EtOAc andfiltered through celite pad. The filtrate was concentrated to give thedesired product which was used for next step without furtherpurification. MS (ESI) 335 (M+H).

Step B. Preparation(R)-9-propyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-9-propyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 245 (M+H).

Examples 261 and 262 Preparation of(R)-2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-7-boromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to the procedures described in Example 220, with thesubstitution of N-(t-butoxycarbonyl)-D-3-bromophenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in Step A andpurified by silica gel chromatography, MeOH/CH2Cl2 (0–4% gradient) togive a mixture of regioisomers. MS (ESI) 371, 373 (M+H) and MS (ESI)371, 373 (M+H).

Examples 263 and 264 Preparation of(R)-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 229 with thesubstitution of a mixture of(R)-2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-7-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 281, 283 (M+H) and 281, 283 (M+H).

Examples 265 and 266 Preparation of(R)-9-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 241 with thesubstitution of a mixture of(R)-2-Benzyl-9-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one and(R)-2-Benzyl-7-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 217 (M+H) and MS (ESI) 217 (M+H).

Examples 267 and 268 Preparation of(R)-9-ethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7-ethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 242 with thesubstitution of a mixture of(R)-2-Benzyl-9-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-7-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 221 (M+H) and MS (ESI) 221 (M+H).

Example 269 Preparation of(R)-9-isopropyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-9-isopropenyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

A degassed mixture of(R)-2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onewith(R)-2-Benzyl-7-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(9-Br:7-Br=1:2, 100 mg, 0.27 mmol), isopropenyl boronic acid (46 mg,0.54 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.013 mmol)and K₂CO₃ (82 mg, 0.59 mmol) in DME (2 mL) and water (0.6 mL) was heatedat 80° C. for 9 h to give dark brownish reaction mixture. The mixturewas then cooled, quenched with 10 m]L of water, extracted with ethylacetate(3×10 mL), dried over MgSO₄, and concentrated in vacuo to givethe desired product as brown oil (No 7-isomeric product was observed).MS (ESI) 333 (M+H). The crude product was utilized for next step withoutfurther purification.

Step B.(R)-9-Isopropyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-9-isopropenyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.The desired product was obtained as a white lyophilate (27 mg, 42% for 2steps). MS (ESI) 245 (M+H).

Examples 270 and 271 Preparation of(R)-9-cyclopropyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and(R)-7-cyclopropyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Step A. Preparation of(R)-2-Benzyl-9-isopropenyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

A degassed mixture of(R)-2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onewith(R)-2-Benzyl-7-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(9-Br: 7-Br=1: 2, 100 mg, 0.27 mmol), isopropenyl boronic acid (46 mg,0.54 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.013 mmol)and K₂CO₃ (82 mg, 0.59 mmol) in DME (2 mL) and water (0.6 mL) was heatedat 80° C. for 9 h to give dark brownish reaction mixture. The mixturewas then cooled, quenched with 10 mL of water, extracted with ethylacetate(3×10 L), dried over MgSO₄, and concentrated in vacuo to give thedesired product as brown oil (No 7-isomeric product was observed). MS(ESI) 333 (M+H). The crude product was utilized for next step withoutfurther purification.

Step B.(R)-8-Ethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 221 with thesubstitution of(R)-2-Benzyl-9-isopropenyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.The desired product was obtained as a white lyophilate (27 mg, 42% for 2steps). MS (ESI) 245 (M+H).

Examples 272 and 273 Preparation of(R)-9-Cyano-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt and of(R)-7-Cyano-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to the procedures described in Example 230, with thesubstitution of a mixture of(R)-2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-7-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 228 (M+H).

Example 274 Preparation of(R)-2-Benzyl-10-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to the procedures described in Example 220, with thesubstitution of N-(t-butoxycarbonyl)-D-2-bromophenylalanine forN-(t-butoxycarbonyl)-D-4-trifluoromethylphenylalanine in Step A andpurified by silica gel chromatography, MeOH/CH2Cl2 (0–4% gradient) togive a the desired product as a yellowish oil. MS (ESI) 371, 373 (M+H).

Example 275 Preparation of(R)-10-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 229 with thesubstitution of a mixture of(R)-2-Benzyl-10-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor(R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one.MS (ESI) 281, 283 (M+H).

Example 276 Preparation of(R)-10-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 266 with thesubstitution of(R)-2-Benzyl-10-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor a mixture of(R)-2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-7-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one,and the substitution of methyl boronic acid for isopropenyl boronic acidin step A. MS (ESI) 217 (M+H).

Example 277 Preparation of(R)-10-ethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 242 with thesubstitution of(R)-2-Benzyl-10-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor a mixture of (R)-2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one and(R)-2-Benzyl-7-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one,and the substitution of trivinylcyclotriboroxane for isopropenyl boronicacid in step A. MS (ESI) 231 (M+H).

Example 278 Preparation of(R)-10-propyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onetrifluoroacetic acid salt

Prepared according to procedures described in Example 242 with thesubstitution of(R)-2-Benzyl-10-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-onefor a mixture of(R)-2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-oneand(R)-2-Benzyl-7-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one,and the substitution of cis-propenyl boronic acid for isopropenylboronic acid in step A. MS (ESI) 245 (M+H).

Example 279 Preparation of(R)-10-bromo-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one

Step A. Preparation of (R)-8trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one

Prepared according to the procedures described in Example 221.Purification by flash column chromatography (SiO₂, 95:5:1 methylenechloride/methanol/triethylamine) yielded the desired product as a whitesolid. MS (ESI) 271 (M+H).

Step B. Preparation of(R)-10-bromo-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one

A solution of (R)-8trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one(245 mg, 0.9 mmol) in H₂SO₄ (2 mL) was treated with NBS (210 mg, 1.17mmol) at room temperature. After 48 h, the reaction mixture was quenchedwith saturated aqueous NaHCO₃ and diluted with EtOAc (15 mL). Thesolution was extracted with EtOAc (50 mL) and the organic layer wasdried over Na₂SO₄, filtered, and concentrated in vacuo to afford ayellow oil. Purification of the oil by flash column chromatography(SiO₂, 96:4:1 methylene chloride/methanol/triethylamine) provided(R)-10-bromo-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one(80 mg, 25%) as an off-white solid. MS (ESI) 349 (M+H).

Example 280 Preparation of(R)-10-ethyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-onehydrochloric acid salt

Step A. Preparation of(R)-2-N-(t-butoxycarbonyl)-10-bromo-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one

Prepared according to procedures described in Example 2 with thesubstitution of(R)-10-bromo-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-onefor(±)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one,at step A. MS (ESI) 359 (M+H).

Step B. Preparation of(R)-10-ethyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-onehydrochloric acid salt

To a mixture of(R)-2-N-(t-butoxycarbonyl)-10-bromo-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one(61 mg, 0.135 mmol) and 2,4,6-trivinylcyclotriboroxane pyridine complex(33 mg, 0.135 mmol) in DME (2 mL) was added K₂CO₃ (20 mg, 0.135 mmol)and water (1 mL). The mixture was degassed under reduced pressure andpurged with argon; tetrakis(triphenylphospine)palladium (0) (20 mg,0.135 mmol) was added. The reaction mixture was heated to 90° C. for 18h. The reaction was cooled to room temperature, and diluted with EtOAc(50 mL). The EtOAc layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford crude alkene 6a as a yellow oil. MS(ESI) 340 (M+H). Crude(R)-2-N-(t-butoxycarbonyl)-10-ethyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-onewas dissolved in EtOH (2 mL) and hydrogenated [10% Pd/C (50 mg), H₂ (30psi)]. The reaction mixture was filtered through diatomaceous earth, andthen purified by flash column chromatography (silica gel, 4:1hexanes/EtOAc). The resulting material was deprotected using 4 N HCl in1,4-dioxane (200 μL, 0.8 mmol), followed by trituration with diethylether, to provide the desired product (18 mg, 40% over 3 steps) as awhite solid. MS (ESI) 299 (M+H).

Example 281 Preparation of(R)-10-methyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-onehydrochloric acid salt

Prepared according to procedures described in Example 280 with thesubstitution of trimethylboroxane for 2,4,6-trivinylcyclotriboroxanepyridine complex and excluding the hydrogenation at step B. MS (ESI) 285(M+H).

Example 282 Preparation of(R)-10-propyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-onehydrochloric acid salt

Prepared according to procedures described in Example 280 with thesubstitution of cis-propenyl boronic acid for2,4,6-trivinylcyclotriboroxane pyridine complex at step B. MS (ESI) 313(M+H).

Examples 283 and 284 Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,10bS)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN,N-diethyl-2-carboxaldehyde-6-trifluoromethylbenzamide

Prepared according to the procedures described in Example 1, Steps A–B,substituting 2-trifluoromethylbenzoic acid for 2-trifluoromethoxybenzoicacid at Step A. MS (ESI) 274 (M+H).

Step B. Preparation of3-hydroxy-7-(trifluoromethyl)isobenzofuran-1(3H)-one

To NN-diethyl-2-carboxaldehyde-6-trifluoromethylbenzamide (23.3 g, 85mmol) from Step A was added 6N aqueous hydrogen chloride (500 mL). Theresulting mixture was warmed to 100° C. and maintained at thistemperature for 12 hr. The reaction was then cooled to 23° C. andextracted with ethyl acetate (×6). The combined organic layers weredried over sodium sulfate, filtered and the filtrate was concentrated.The resulting residue was triturated with hexanes and dried in a vacuumoven to afford 3-hydroxy-7-(trifluoromethyl)isobenzofuran-1(3H)-one(16.2 g, 88%) as a beige solid. MS (ESI) 219 (M+H).

Step C. Preparation of2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one

To 3-hydroxy-7-(trifluoromethyl)isobenzofuran-1(3H)-one (5.6 g, 25.7mmol) from Step B in 10% acetic acid in 1,2-dichloroethane (250 mL) wasadded N-(tert-butoxycarbonyl)ethylenediamine (3.7 mL, 23.4 mmol) andsodium triacetoxyborohydride (7.4 g, 35.1 mmol). The resulting mixturewas warmed to 50° C. and maintained at this temperature for 14 hr. Thereaction was cooled to 23° C., diluted with saturated aqueous sodiumchloride and extracted with ethyl acetate (×3). The combined organiclayers were dried over sodium sulfate, filtered and the filtrate wasconcentrated. The resulting residue was purified by flash columnchromatography (SiO₂, 0–80% ethyl acetate in hexanes) to afford2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one(7.9 g, 89%) as an off-white oily solid. MS (ESI) 345 (M+H).

Step D. Preparation of(±)-2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1-(1-hydroxyethyl)-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one

To2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one(2.31 g, 6.71 mmol) from Step C in tetrahydrofuran at −78° C. was addedsec-butyllithium (12.3 mL, 14.8 mmol; ACROS, titrated withdiphenylacetic acid, 1.2 M) in cyclohexane/hexane (92/8) in one portion.After stirring the reaction at −78° C. for 15 min, acetaldehyde (1.88mL, 33.6 mmol) was added in one portion. The brown-green solution waswarmed to 0° C. over 5 min and was then quenched with aqueous hydrogenchloride (1N) and saturated aqueous sodium chloride. The mixture wasextracted with ethyl acetate (×3), and the combined organic layers weredried over sodium sulfate, filtered and the filtrate was concentrated.The resulting residue was purified by flash column chromatography (SiO₂,0–50% ethyl acetate in hexanes) to afford(±)-2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1-(1-hydroxyethyl)-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one(2.2 g, 84%) as a white foam-like solid. MS (ESI) 389 (M+H).

Step E. Preparation of(±)-2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1-(1-oxoethyl)-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one

To(±)-2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1-(1-hydroxyethyl)-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one(2.2 g, 5.7 mmol) from Step C in dichloromethane at 23° C. was addedDess-Martin periodinane (3.4 g, 7.9 mmol) in one portion. After 20 min,the reaction was quenched with methanol (10 mL) and concentrated. Theresulting white mixture was purified by flash column flash columnchromatography (SiO₂, 0–50% ethyl acetate in hexanes) to afford(±)-2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1-(1-oxoethyl)-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one(1.9 g, 86%) as a white solid. MS (ESI) 387 (M+H).

Step F. Preparation ofN-(t-butoxycarbonyl)-3,4-dihydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Concentrated aqueous hydrogen chloride (5 mL) was added to a mixture ofdiethyl ether (20 mL) and(±)-2-[2-[(tert-butoxycarbonyl)amino]ethyl]-1-(1-oxoethyl)-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one(1.9 g, 4.9 mmol). The resulting mixture was stirred for 5 min andbecame a yellow solution. The solution was concentrated to dryness, andtoluene was added (5 mL). The mixture was again concentrated to dryness,and this procedure was repeated. Finally, the residue was treated withdichloromethane (5 mL) and concentrated to a yellow orange solid.Di-tert-butyl dicarbonate (4.8 g, 22 mmol) was added to the residue, andthe mixture was warmed to 55° C. To this mixture was added4-(dimethylamino)-pyridine (1.2 g, 9.8 mmol). After 5 min, the orangebrown solution was directly purified by flash column chromatography(SiO₂, 0–30% ethyl acetate in hexanes) to affordN-(t-butoxycarbonyl)-3,4-dihydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(1.5 g, 83%) as a yellow solid. MS (ESI) 369 (M+H).

Step G. Preparation ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To a solution ofN-(t-butoxycarbonyl)-3,4-dihydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(0.20 g, 0.54 mmol) in methanol (10 mL) was added palladium on carbon(20 mg, 10 wt %; Aldrich). The resulting mixture was degassed (vacuumthen argon, ×3) and subjected to a hydrogen atmosphere (60 psi) for 12hr. The mixture was then filtered, and the filtrate was concentrated.The resulting residue was purified by flash column chromatography (SiO₂,0–50% ethyl acetate in hexanes) to affordN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(0.19 g, 94%) as a white solid. MS (ESI) 371 (M+H).

Step H. Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,10bS)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

The mixture of enantiomers contained inN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(81 mg, 0.22 mmol) was separated by chiral HPLC using an AD column with90% heptane containing 0.1% diethylamine and 10% 1:1 MeOH:EtOHcontaining 0.1% diethylamine. The resulting solids were individuallyrepurified by ISCO flash column chromatography (SiO₂, 0–50% ethylacetate in hexanes) to yield 35 mg of the (1S,10bR) enantiomer and 36 mgof the (1R,10bS) enantiomer as white solids. The solids wereindividually dissolved in dry ether (1 mL)and the treated withhydrochloric acid (1 mL). The reactions were stirred for 5 min and thenconc. in vacuo to a white solid. The solids were dissolved in water andlyophilized to yield 28 mg (quant) of the (1S,10bR) enantiomer and 28 mg(93%) of the (1R,10bS) enantiomer as white solids. MS (ESI) 271 (M−Cl).

Examples 285 and 286 Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-1-ethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,10bS)-1,3,4,10b-tetrahydro-1-ethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedures described in Example 283, stepsA–H, with substitution of propionaldehyde for acetaldehyde at step D andN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-ethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneat Step H. MS (ESI) 285 (M-C1).

Examples 287 and 288 Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-1-propyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(LR,10bS)-1,3,4,10b-tetrahydro-1-propyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedures described in Example 283, stepsA–H, with substitution of butyraldehyde for acetaldehyde at step D,N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-propyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneat Step H, and 80% heptane containing 0.1% diethylamine for 90% heptanecontaining 0.1% diethylamine at step H. MS (ESI) 299 (M−Cl).

Examples 289 and 290 Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-1-cyclopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,10bS)-1,3,4,10b-tetrahydro-1-cyclopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedures described in Example 283, stepsA–H, with substitution of cyclopropanecarbaldehyde for acetaldehyde atstep D andN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-cyclopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazin[2,1-a]isoindol-6(2H)-oneat Step H. MS (ESI) 297 (M−Cl).

Examples 291 and 292 Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-1-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,10bS)-1,3,4,10b-tetrahydro-1-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation of(±)-2-[2-[bis(tert-butoxycarbonyl)amino]ethyl]-1-(1-oxo-2-methylpropyl)-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one

Prepared according to the procedures of Example 283, Steps A–F,substituting 2-methylpropionaldehyde for acetaldehyde at Step D. MS(ESI) 515 (M+H).

Step B. Preparation of(±)-1,3,4,10b-tetrahydro-1-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To(±)-2-[2-[bis(tert-butoxycarbonyl)amino]ethyl]-1-(1-oxo-2-methylpropyl)-1,3-dihydro-4-trifluoromethyl-isoindol-3(1H)-one(277 mg, 0.54 mmol) was added concentrated aqueous hydrogen chloride Theresulting mixture was stirred for 35 min and became a yellow solution.The solution was concentrated to dryness, and toluene was added (5 mL).The mixture was again concentrated to dryness, and this procedure wasrepeated. Finally, the residue was treated with dichloromethane (5 mL)and concentrated to a yellow orange solid. The residue was dissolved inmethanol (20 mL) and palladium on carbon (20 mg, 10 wt % l; Aldrich) wasadded in one portion under a stream of argon. The resulting mixture wasdegassed (vacuum then argon, ×3) and subjected a hydrogen atmosphere (60psi) for 11 days. The mixture was then filtered and the filtrate wasconcentrated. The residue was treated with saturated aqueous ammoniumhydroxide, concentrated, and the resulting white solid was purified byflash column chromatography (SiO₂, 0–50% ethyl acetate in hexanes) toafford(±)-1,3,4,10b-tetrahydro-1-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(151 mg, 94%) as a white residue. MS (ESI) 299 (M+H).

Step C. Preparation ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

To(±)-1,3,4,10b-tetrahydro-1-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(0.151 g, 0.51 mmol) was added di-tert-butyl dicarbonate (0.59 g, 2.7mmol), and the mixture was warmed to 55° C. To this mixture was added4-(dimethylamino)-pyridine (0.12 g, 1.0 mmol). After 5 min, the orangebrown solution was directly purified by flash column chromatography(SiO₂, 0–50% ethyl acetate in hexanes) to affordN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-isopropyl-7trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(0.089 g, 44%) as a yellow solid. MS (ESI) 399 (M+H).

Step C. Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-1-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,10bS)-1,3,4,10b-tetrahydro-1-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedure described in Example 283, Step H,substitutingN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-isopropyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 299 (M−Cl).

Example 293 and 294 Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,10bS)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

ToN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(364 mg, 0.98 mmol) was added concentrated aqueous hydrogen chloride (5mL). The resulting mixture was stirred for five minutes and thenconcentrated. The resulting residue was treated with concentratedaqueous sulfuric acid (2.0 mL) and N-bromosuccinimide (193 mg, 1.1mmol). The resulting brown solution was degassed (vacuum then argon),covered with aluminum foil and stirred in the dark for 24 h. Thereaction was then diluted with ice water and basified with saturatedaqueous sodium bicarbonate. The resulting mixture was diluted with ethylacetate (15 mL) and treated with di-tert-butyl dicarbonate (excess).After 1 hr, the reaction was washed with ethyl acetate (3×50 mL), andthe combined organic layers were dried over sodium sulfate, filtered,and concentrated. The resulting residue was purified by flash columnchromatography (SiO₂, 0–30% ethyl acetate in hexanes) to affordN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(261 mg, 59%) as a white foam-like solid. MS (ESI) 449, 451 (M+H).

Step B. Preparation ofN-(t-butoxycarbonyl)-(1S,10bR)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneandN-(t-butoxycarbonyl)-(11R,10bS)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

The mixture of enantiomers contained inN-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(498 mg, 1.1 mmol) was separated by chiral HPLC using an AD column with90% heptane with 0.1% diethylamine and 10% 1:1 MeOH:EtOH with 0.1%diethylamine. The resulting solids were individually repurified by ISCOflash column chromatography (SiO₂, 0–50% ethyl acetate in hexanes) toyield 155 mg of the (1S,10bR) enantiomer and 156 mg of the (1R,10bS)enantiomer as white solids. MS (ESI) 449, 451 (M+H).

Step C. Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt and(1R,10bS)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

ToN-(t-butoxycarbonyl)-(1S,10bR)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(16.7 mg, 0.037 mmol) andN-(t-butoxycarbonyl)-(1R,10bS)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one(17.8 mg, 0.040 mmol) was added (in separate flasks) dry ether (1 mL)andhydrochloric acid (1 mL). The reactions were stirred for 5 min and thenconc. in vacuo to a white solid. The solids were dissolved in water andlyophilized to yield 12 mg (84%) of the (1S,10bR) enantiomer and 13 mg(88%) of the (1R,10bS) enantiomer as white solids. MS (ESI) 271 (M−Cl).

Example 295 Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-9-ethyl-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Step A. Preparation ofN-(t-butoxycarbonyl)-(1S,10bR)-1,3,4,10b-tetrahydro-9-ethyl-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one

Prepared according to the procedures of Example 122, Steps B–C,substitutingN-(t-butoxycarbonyl)-(1S,10bR)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onefor N,N-diethyl-4-bromo-2-(trifluormethoxy)benzamide at Step B. MS (ESI)399 (M+H).

Step B. Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedures of Example 2, Step B, substitutingN-(t-butoxycarbonyl)-(1S,10bR)-1,3,4,10b-tetrahydro-9-ethyl-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-oneforN-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one.MS (ESI) 299 (M−Cl).

Example 296 Preparation of(1S,10bR)-1,3,4,10b-tetrahydro-9-isopropyl-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt

Prepared according to the procedures of Example 295, Steps A–B,substituting isopropenylboronic acid for 2,4,6-trivinylcyclotriboroxanepyridine complex at Step A. MS (ESI) 313 (M+H).

While it is apparent that the embodiments of the invention hereindisclosed are well suited to fulfill the objectives stated above, itwill be appreciated that numerous modifications and other embodimentsmay be implemented by those skilled in the art, and it is intended thatthe appended claims cover all such modifications and embodiments thatfall within the true spirit and scope of the present invention.

A number of references have been cited and the entire disclosures ofwhich are incorporated herein by reference.

1. A compound according to the following formula:

or stereoisomers or pharmaceutically acceptable salt forms thereof,wherein: R¹ is selected from the group consisting of H and CH₃; R⁸ isselected from the group consisting of alkyl, perfluoroalkyl andcycloalkyl; and R¹⁰ is selected from the group consisting of H andalkyl.
 2. The compound according to claim 1, wherein R¹ is H.
 3. Thecompound according to claim 2, wherein R⁸ is selected from the groupconsisting of CF₃ and cyclopropyl.
 4. The compound according to claim 1,wherein the compound is selected from the group consisting of(R)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-9-ethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onetrifluoroacetic acid salt;(R)-1,3,4,10b-tetrahydro-9-(propyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-9-(3-pentyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-9-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-7-cyclopropyl-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-9-ethyl-7-isopropyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-7,9-diethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-9-ethyl-7-propyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-9-ethyl-7-(2-methylpropyl)-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-7-cyclopentyl-9-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-7-ethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-7-cyclopropyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(R)-1,3,4,10b-tetrahydro-7-cyclopentyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(1S,10bR)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt;(1S,10bR)-1,3,4,10b-tetrahydro-9-ethyl-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-onehydrochloric acid salt; and(1S,10bR)-1,3,4,10b-tetrahydro-9-isopropyl-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one hydrochloric acid salt.
 5. A compound according to thefollowing formula:

or stereoisomers or pharmaceutically acceptable salt forms thereof,wherein: A is CR¹R²; B is CR⁴R⁵; D is CR⁶R⁷, CO or SO₂; m is 1 or 2; nis 1 or 2; R¹, R², R⁴, R⁵, R⁶ and R⁷ are each independently selectedfrom the group consisting of H, C₁–C⁴ alkyl, C₂–C₄ alkenyl, cycloalkyl,alkylaryl, alkylheteroaryl, aryl and heteroaryl, wherein each C₂–C₄alkyl, alkylaryl, alkylheteroaryl, aryl and heteroaryl, is optionally besubstituted with one or more hydroxy, alkyl, alkenyl, alkynyl, oxyalkyl,oxyalkenyl, oxyalkynyl, oxycycloalkyl, oxyperfluoroalkyl, —OCF₃,thioalkyl, thioalkenyl, thioalkynyl, thioaryl, thioheteroaryl,thiocycloalkyl, aryl, heteroaryl, heterocyclyl, nitrile, halogen,carboaminoalkyl, carboaminoalkenyl, carboaminoakynyl, carboaminoaryl,carboaminocycloalkyl, carboalkyl, carboalkenyl, carboalkynyl, carboaryl,carbocycloalkyl, carboheterocyclyl, carboheteroaryl,carboaminoheterocyclyl, carboaminoheteroaryl, aminocarboalkyl,aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboaminoheterocyclyl,aminocarboaminoheteroaryl, perfluoroalkyl, CF₃, perfluoroalkenyl,perfluoroalkynyl, oxyaryl, oxyheteroaryl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl,aminoheterocyclyl, alkylamino, alkenylamino, alkynylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkyl, carboxyalkenyl,carboxyalkynyl, carboxyaryl, carboxyheteroaryl, carboxycycloalkyl,carboxyheterocyclyl, oxycarboalkyl, oxycarboalkenyl, oxycarboalkynyl,oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,oxycarboheterocyclyl,sulfoaminoalkyl, sulfoaminoalkenyl,sulfoaminoalykynyl, sulfoaminoaryl, sulfoaminoheteroaryl,sulfoaminocycloalkyl, sulfoaminoheterocyclyl, aminosulfoalkyl,aminosulfoalkenyl, aminosulfoalkynyl, aminosulfocycloalkyl,aminosulfoaryl, aminosulfoheteroaryl, aminosulfoheterocyclyl,sulfoalkyl, sulfoalkenyl, sulfoalkynyl, sulfocycloalkyl, sulfoaryl,sulfoheteroaryl, sulfoheterocyclyl and cycloalkyl; R³ is selected fromthe group consisting of H, C₁–C₄ alkyl, cycloalkyl, alkylaryl,alkylheteroaryl, aryl and heteroaryl; R⁸, R⁹, R¹⁰ and R¹¹ are eachindependently selected from the group consisting of H, hydroxy, alkyl,alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, oxycycloalkyl,oxyperfluoroalkyl, —OCF₃, thioalkyl, thioalkenyl, thioalkynyl, thioaryl,thioheteroaryl, thiocycloalkyl, aryl, heteroaryl, heterocyclyl, nitrile,halogen, carboaminoalkyl, carboaminoalkenyl, carboaminoakynyl,carboaminoaryl, carboaminocycloalkyl, carboalkyl, carboalkenyl,carboalkynyl, carboaryl, carbocycloalkyl, carboheterocyclyl,carboheteroaryl, carboaminoheterocyclyl, carboaminoheteroaryl,aminocarboalkyl, aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboaminoheterocyclyl,aminocarboaminoheteroaryl, perfluoroalkyl, CF₃, perfluoroalkenyl,perfluoroalkynyl, oxyaryl, oxyheteroaryl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl,aminoheterocyclyl, alkylamino, alkenylamino, alkynylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkyl, carboxyalkenyl,carboxyalkynyl, carboxyaryl, carboxyheteroaryl, carboxycycloalkyl,carboxyheterocyclyl, oxycarboalkyl, oxycarboalkenyl, oxycarboalkynyl,oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,oxycarboheterocyclyl,sulfoaminoalkyl, sulfoaminoalkenyl,sulfoaminoalykynyl, sulfoaminoaryl, sulfoaminoheteroaryl,sulfoaminocycloalkyl, sulfoaminoheterocyclyl, aminosulfoalkyl,aminosulfoalkenyl, aminosulfoalkynyl, aminosulfocycloalkyl,aminosulfoaryl, aminosulfoheteroaryl, aminosulfoheterocyclyl,sulfoalkyl, sulfoalkenyl, sulfoalkynyl, sulfocycloalkyl, sulfoaryl,sulfoheteroaryl, sulfoheterocyclyl and cycloalkyl, wherein each alkyl,alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, oxycycloalkyl,thioalkyl, thioalkenyl, thioalkynyl, thioaryl, thioheteroaryl,thiocycloalkyl, aryl, heteroaryl, heterocyclyl, carboaminoalkyl,carboaminoalkenyl, carboaminoakynyl, carboaminoaryl,carboaminocycloalkyl, carboalkyl, carboalkenyl, carboalkynyl, carboaryl,carbocycloalkyl, carboheterocyclyl, carboheteroaryl,carboaminoheterocyclyl, carboaminoheteroaryl, aminocarboalkyl,aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboaminoheterocyclyl,aminocarboaminoheteroaryl, oxyaryl, oxyheteroaryl, aminoalkyl,aminoalkenyl, aminoalkynyl, amino aryl, aminoheteroaryl,aminocycloalkyl, aminoheterocyclyl, alkylamino, alkenylamino,alkynylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkyl,carboxyalkenyl, carboxyalkynyl, carboxyaryl, carboxyheteroaryl,carboxycycloalkyl, carboxyheterocyclyl, oxycarboalkyl, oxycarboalkenyl,oxycarboalkynyl, oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,oxycarboheterocyclyl,sulfoaminoalkyl, sulfoaminoalkenyl,sulfoaminoalykynyl, sulfoaminoaryl, sulfoaminoheteroaryl,sulfoaminocycloalkyl, sulfoaminoheterocyclyl, aminosulfoalkyl,aminosulfoalkenyl, aminosulfoalkynyl, aminosulfocycloalkyl,aminosulfoaryl aminosulfoheteroaryl, aminosulfoheterocyclyl, sulfoalkyl,sulfoalkenyl, sulfoalkynyl, sulfocycloalkyl, sulfoaryl, sulfoheteroaryl,sulfoheterocyclyl and cycloalkyl, is optionally substituted with one ormore hydroxy, alkyl, alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl,oxycycloalkyl, oxyperfluoroalkyl, —OCF₃, thioalkyl, thioalkenyl,thioalkynyl, thioaryl, thioheteroaryl, thiocycloalkyl, aryl, heteroaryl,heterocyclyl, nitrile, halogen, carboaminoalkyl, carboaminoalkenyl,carboaminoakynyl, carboaminoaryl, carboaminocycloalkyl, carboalkyl,carboalkenyl, carboalkynyl, carboaryl, carbocycloalkyl,carboheterocyclyl, carboheteroaryl, carboaminoheterocyclyl,carboaminoheteroaryl, aminocarboalkyl, aminocarboalkenyl,aminocarboalkynyl, aminocarboaryl, aminocarbocycloalkyl,aminocarboheterocyclyl, aminocarboheteroaryl, oxycarboaminoalkyl,oxycarboaminoalkenyl, oxycarboaminoalkynyl, oxycarboaminoaryl,oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboaminoheterocyclyl,aminocarboaminoheteroaryl, perfluoroalkyl, CF₃, perfluoroalkenyl,perfluoroalkynyl, oxyaryl, oxyheteroaryl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl,aminoheterocyclyl, alkylamino, alkenylamino, alkynylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkyl, carboxyalkenyl,carboxyalkynyl, carboxyaryl, carboxyheteroaryl, carboxycycloalkyl,carboxyheterocyclyl, oxycarboalkyl, oxycarboalkenyl, oxycarboalkynyl,oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,oxycarboheterocyclyl,sulfoaminoalkyl, sulfoaminoalkenyl,sulfoaminoalykynyl, sulfoaminoaryl, sulfoaminoheteroaryl,sulfoaminocycloalkyl, sulfoaminoheterocyclyl, aminosulfoalkyl,aminosulfoalkenyl, aminosulfoalkynyl, aminosulfocycloalkyl,aminosulfoaryl, aminosulfoheteroaryl, aminosulfoheterocyclyl,sulfoalkyl, sulfoalkenyl, sulfoalkynyl, sulfocycloalkyl, sulfoaryl,sulfoheteroaryl, sulfoheterocyclyl and cycloalkyl, optionally R⁸ and R⁹,R⁹ and R¹⁰ or R¹⁰ and R¹¹ are taken together to form a cycloalkyl,heterocyclyl, aryl or heteroaryl; R¹² and R¹³ are each independentlyselected from the group consisting of H, C₁–C₄ alkyl, hydroxy, oxyalkyl,cycloalkyl, aryl and heteroaryl; and R¹⁴ and R¹⁵ are each independentlyselected from the group consisting of H, C₁–C₄ alkyl, cycloalkyl, aryland alkylaryl, with the following proviso the compound is not

wherein R^(A) is H or C₁–C₆ alkyl; R^(B) is H, C₁–C₆ alkyl, C₁–C₆alkoxy, hydroxy, halo or CF₃; R^(D) is H, C₁–C₆ alkyl or benzyl.
 6. Thecompound according to claim 5, wherein R⁸, R⁹, R¹⁰ and R¹¹ are eachindependently selected from the group consisting of H, hydroxy, alkyl,alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, oxycycloalkyl,oxyperfluoroalkyl, —OCF₃, thioalkyl, thioalkenyl, thioalkynyl, thioaryl,thioheteroaryl, thiocycloalkyl, aryl, heteroaryl, heterocyclyl, nitrile,halogen, carboaminoalkyl, carboaminoalkenyl, carboaminoakynyl,carboaminoaryl, carboaminocycloalkyl, carboheterocyclyl,carboheteroaryl, carboaminoheterocyclyl, carboaminoheteroaryl,aminocarboalkyl, aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,aminocarboaminoheterocyclyl, aminocarboaminoheteroaryl, perfluoroalkyl,CF₃, perfluoroalkenyl, perfluoroalkynyl, oxyaryl, oxyheteroaryl,aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl,aminocycloalkyl, alkylamino, alkenylamino, alkynylamino, arylamino,heteroarylamino, cycloalkylamino and cycloalkyl, wherein each alkyl,alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, oxycycloalkyl,thioalkyl, thioalkenyl, thioalkynyl, thioaryl, thioheteroaryl,thiocycloalkyl, aryl, heteroaryl, heterocyclyl, carboaminoalkyl,carboaminoalkenyl, carboaminoakynyl, carboaminoaryl,carboaminocycloalkyl, carboheterocyclyl, carboheteroaryl,carboaminoheterocyclyl, carboaminoheteroaryl, aminocarboalkyl,aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,aminocarboaminoheterocyclyl, aminocarboaminoheteroaryl, oxyaryl,oxyheteroaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl,aminoheteroaryl, aminocycloalkyl, alkylamino, alkenylamino,alkynylamino, arylamino, heteroarylamino, cycloalkylamino andcycloalkyl, is optionally substituted with one or more hydroxy, alkyl,alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, oxycycloalkyl,oxyperfluoroalkyl, —OCF₃, thioalkyl, thioalkenyl, thioalkynyl, thioaryl,thioheteroaryl, thiocycloalkyl, aryl, heteroaryl, heterocyclyl, amino,nitrile, halogen, perfluoroalkyl, —CF₃, perfluoroalkenyl,perfluoroalkynyl, oxyaryl, oxyheteroaryl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl, alkylamino,alkenylamino, alkynylamino, arylamino, heteroarylamino, cycloalkylaminoand cycloalkyl.
 7. The compound according to claim 6, wherein R⁸, R⁹,R¹⁰ and R¹¹ are each independently selected from the group consisting ofH, hydroxy, alkyl, alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl,oxycycloalkyl, oxyperfluoroalkyl, —OCF₃, thioalkyl, thioalkenyl,thioalkynyl, thioaryl, thioheteroaryl, thiocycloalkyl, aryl, heteroaryl,heterocyclyl, halogen, perfluoroalkyl, —CF₃, oxyaryl, oxyheteroaryl,aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl,aminocycloalkyl and cycloalkyl.
 8. The compounds according to claim 7,wherein: R⁴ is H; and R⁵ is H.
 9. The compounds according to claim 8,wherein: R¹⁴ is H; R¹⁵ is H; and D is CR⁶R⁷.
 10. The compounds accordingto claim 9, wherein: R³, R⁶ and R⁷ are H.
 11. The compounds according toclaim 10, wherein: R¹ and R² are independently selected from the groupconsisting of H and C₁–C₄ alkyl; m is 1; and n is
 1. 12. The compoundsaccording to claim 11, wherein: R¹ and R² are H.
 13. A compoundaccording to the following formula:

or stereoisomers or pharmaceutically acceptable salt forms thereof,wherein: A is CR¹R²; B is CR⁴R⁵; m is 1 or 2; n is 1 or 2; R¹, R², R⁴,R⁵, R⁶ and R⁷ are each independently selected from the group consistingof H, C₁–C₄ alkyl, C₂–C₄ alkenyl, cycloalkyl, alkylaryl,alkylheteroaryl, aryl and heteroaryl, wherein each C₁–C₄ alkyl,alkylaryl, alkylheteroaryl, aryl and heteroaryl, is optionallysubstituted with one or more hydroxy, alkyl, alkenyl, alkynyl, oxyalkyl,oxyalkenyl, oxyalkynyl, oxycycloalkyl, oxyperfluoroalkyl, —OCF₃,thioalkyl, thioalkenyl, thioalkynyl, thioaryl, thioheteroaryl,thiocycloalkyl, aryl, heteroaryl, heterocyclyl, nitrile, halogen,carboaminoalkyl, carboaminoalkenyl, carboaminoakynyl, carboaminoaryl,carboaminocycloalkyl, carboalkyl, carboalkenyl, carboalkynyl, carboaryl,carbocycloalkyl, carboheterocyclyl, carboheteroaryl,carboaminoheterocyclyl, carboaminoheteroaryl, aminocarboalkyl,aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboaminoheterocyclyl,aminocarboaminoheteroaryl, perfluoroalkyl, CF₃, perfluoroalkenyl,perfluoroalkynyl, oxyaryl, oxyheteroaryl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl,aminoheterocyclyl, alkylamino, alkenylamino, alkynylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkyl, carboxyalkenyl,carboxyalkynyl, carboxyaryl, carboxyheteroaryl, carboxycycloalkyl,carboxyheterocyclyl, oxycarboalkenyl, oxycarboalkenyl, oxycarboalkynyl,oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,oxycarboheterocyclyl, sulfoaminoalkyl, suifoaminoalkenyl,sulfoaminoalykynyl, sulfoaminoaryl, sulfoaminoheteroaryl,suffoaminocycloalkyl, sulfoaminoheterocyclyl, aminosulfoalkyl,aminosulfoalkenyl, aminosulfoalkynyl, aminosulfocycloalkyl,aminosulfoaryl, aminosulfoheteroaryl, aminosulfoheterocyclyl,sulfoalkyl, sulfoalkenyl, sulfoalkynyl, sulfocycloalkyl, sulfoaryl,sulfoheteroaryl, sulfoheterocyclyl and cycloalkyl; R³ is selected fromthe group consisting of H, C₁–C₄ alkyl, cycloalkyl, alkylaryl,alkylheteroaryl, aryl and heteroaryl; R⁸ is selected from the groupconsisting of H, alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl,oxycycloalkyl, oxyperfluoroalkyl, —OCF₃, thioalkyl, thioalkenyl,thioalkynyl, thioaryl, thioheteroaryl, thiocycloalkyl, heterocyclyl,nitrile, halogen, oxyaryl, oxyheteroaryl, sulfoalkyl, sulfoalkenyl,sulfoalkynyl, sulfocycloalkyl, sulfoaryl, sulfoheteroaryl andsulfoheterocyclyl; R⁹ is selected from the group consisting of H, alkyl,alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, oxyaryl,oxyheteroaryl, oxycycloalkyl, oxyperfluoroalkyl, —OCF₃, thioalkyl,thioalkenyl, thioalkynyl, thioaryl, thioheteroaryl, thiocycloalkyl,aryl, heteroaryl, halogen, aminoaryl, aminoheteroaryl and cycloalkyl;R¹⁰ is selected from the group consisting of H, alkyl, alkenyl,alkylnyl, oxyalkyl, oxyalkenyl, oxyalkynyl, oxycycloalkyl,oxyperfluoroalkyl, —OCF₃, thioalkyl, thioalkenyl, thioalkynyl, thioaryl,thioheteroaryl, thiocycloalkyl, aryl, heteroaryl, nitrite, halogen,oxyaryl, oxyheteroaryl, aminoalkyl, aminoalkenyl, aminoalkynyl,aminoaryl, aminoheteroaryl, aminocycloalkyl, aminoheterocyclyl andcycloalkyl, optionally when R¹⁰ is cycloalkyl, R⁸ is additionallyselected from the group consisting of alkyl, perfluoroalkyl andcycloalkyl; R¹¹ is selected from the group consisting of H, alkyl,alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, oxycycloalkyl,oxyperfluoroalkyl, —OCF₃, oxyaryl, oxyheteroaryl, thioalkyl,thioalkenyl, thioalkynyl, thioaryl, thioheteroaryl, thiocycloalkyl,aryl, halogen and cycloalkyl, wherein each alkyl, alkenyl, alkynyl,oxyalkyl, oxyalkenyl, oxyalkynyl, oxycycloalkyl, thioalkyl, thioalkenyl,thioalkynyl, thioaryl, thioheteroaryl, thiocycloalkyl, aryl, heteroaryl,heterocyclyl, oxyaryl, oxyheteroaryl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl,aminoheterocyclyl, sulfoalkyl, sulfoalkenyl, sulfoalkynyl,sulfocycloalkyl, sulfoaryl, sulfoheteroaryl, sulfoheterocyclyl andcycloalkyl of R⁸, R⁹, R¹⁰ and R¹¹ is optionally substituted with one ormore hydroxy, alkyl, alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl,oxycycloalkyl, oxyperfluoroalkyl, —OCF₃, thioalkyl, thioalkenyl,thioalkynyl, thioaryl, thioheteroaryl, thiocycloalkyl, aryl, heteroaryl,heterocyclyl, nitrile, halogen, carboaminoalkyl, carboaminoalkenyl,carboaminoakynyl, carboaminoaryl, carboaminocycloalkyl, carboalkyl,carboalkenyl, carboalkynyl, carboaryl, carbocycloalkyl,carboheterocyclyl, carboheteroaryl, carboaminoheterocyclyl,carboaminoheteroaryl, aminocarboalkyl, aminocarboalkenyl,aminocarboalkynyl, aminocarboaryl, aminocarbocycloalkyl,aminocarboheterocyclyl, aminocarboheteroaryl, oxycarboaminoalkyl,oxycarboaminoalkenyl, oxycarboaminoalkynyl, oxycarboaminoaryl,oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboaminoheterocyclyl,aminocarboaminoheteroaryl, perfluoroalkyl, CF₃, perfluoroalkenyl,perfluoroalkynyl, oxyaryl, oxyheteroaryl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl,aminoheterocyclyl, alkylamino, alkenylamino, alkynylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkyl, carboxyalkenyl,carboxyalkynyl, carboxyaryl, carboxyheteroaryl, carboxycycloalkyl,carboxyheterocyclyl, oxycarboalkenyl, oxycarboalkenyl, oxycarboalkynyl,oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,oxycarboheterocyclyl,sulfoaminoalkyl, sulfoaminoalkenyl,sulfoaminoalykynyl, sulfoaminoaryl, sulfoaminoheteroaryl,sulfoaminocycloalkyl, sulfoaminoheterocyclyl, aminosulfoalkyl,aminosulfoalkenyl, aminosulfoalkynyl, aminosulfocycloalkyl,aminosulfoaryl, aminosulfoheteroaryl, aminosulfoheterocyclyl,sulfoalkyl, sulfoalkenyl, sulfoalkynyl, sulfocycloalkyl, sulfoaryl,sulfoheteroaryl, sulfoheterocyclyl and cycloalkyl, optionally R⁸ andR⁹or R¹⁰ and R¹¹ may be taken together to form a cycloalkyl,heterocyclyl, aryl or heteroaryl, with the following proviso thecompound is not

wherein R^(A) is H or C₁–C₆ alkyl; R^(B) is H, C₁–C₆ alkoxy, hydroxy,halo or CF₃; R^(D) is H, C₁–C₆ alkyl or benzyl.
 14. The compoundsaccording to claim 13, wherein: R⁹ is selected from the group consistingof selected from the group consisting of H, alkyl, oxyalkyl and halogen;and R¹¹ is selected from the group consisting of selected from the groupconsisting of H, alkyl, oxyalkyl, thioalkyl halogen and cycloalkyl,wherein each alkyl, oxyalkyl, thioalkyl and cycloalkyl of R⁹ and R¹¹, isoptionally substituted with one or more hydroxy, alkyl, alkenyl,alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, oxycycloalkyl,oxyperfluoroalkyl, —OCF₃, thioalkyl, thioalkenyl, thioalkynyl, thioaryl,thioheteroaryl, thiocycloalkyl, aryl, heteroaryl, heterocyclyl, amino,nitrile, halogen, perfluoroalkyl, —CF₃, perfluoroalkenyl,perfluoroalkynyl, oxyaryl, oxyheteroaryl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl, alkylamino,alkenylamino, alkynylamino, arylamino, heteroarylamino, cycloalkylaminoand cycloalkyl.
 15. The compounds according to claim 14, wherein: R⁸ isselected from the group consisting of oxyalkyl, oxyperfluoroalkyl,—OCF₃, thioalkyl and halogen; and R¹⁰ is selected from the groupconsisting of H, alkyl, oxyalkyl, thioalkyl, and cycloalkyl, optionallywhen R¹⁰ is cycloalkyl, R⁸ is additionally selected from the groupconsisting of alkyl, perfluoroalkyl and cycloalkyl; wherein each alkyl,oxyalkyl, thioalkyl and cycloalkyl of R⁸ and R¹⁰, is optionallysubstituted with one or more hydroxy, alkyl, alkenyl, alkynyl, oxyalkyl,oxyalkenyl, oxyalkynyl, oxycycloalkyl, oxyperfluoroalkyl, —OCF₃,thioalkyl, thioalkenyl, thioalkynyl, thioaryl, thioheteroaryl,thiocycloalkyl, aryl, heteroaryl, heterocyclyl, amino, nitrile, halogen,perfluoroalkyl, —CF₃, perfluoroalkenyl, perfluoroalkynyl, oxyaryl,oxyheteroaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl,aminoheteroaryl, aminocycloalkyl, alkylamino, alkenylamino,alkynylamino, arylamino, heteroarylamino, cycloalkylamino andcycloalkyl.
 16. The compounds according to claim 15, wherein: R⁴ is H;and R is H.
 17. The compounds according to claim 16, wherein: R³, R⁶ andR⁷ is H.
 18. The compounds according to claim 17, wherein: R¹ and R² areindependently selected from the group consisting of H and C₁–C₄ alkyl; mis 1; and n is
 1. 19. The compounds according to claim 18, wherein: R¹,R², R⁹ and R¹¹ are H.